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Joanne K Tobacman - One of the best experts on this subject based on the ideXlab platform.
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aBstract B21 <B>ArylsulfataseB> B arsB is reduced in melanoma metastases and decline in arsB increases programmed death ligand pdl 1
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:<B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines. C4S increased as ARSB declined in the cultured melanoma cell lines. Decline in ARSB was associated with increased expression of chondroitin sulfate proteoglycan (CSPG) 4 and matrix metalloproteinase (MMP) 2. The increase in CSPG4 was attriButed to reduced Binding of galectin-3 with C4S, and the increase of MMP2 was attriButed to inhiBition of SHP2, the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), due to increased Binding with C4S. The invasiveness of the cultured melanoma cells increased when ARSB was silenced By siRNA. To further address the role of ARSB in melanoma progression, metastatic melanoma tissue was oBtained from the Biorepository of the University of Illinois at Chicago. ARSB activity and expression were reduced in the metastatic tissues and ARSB promoter methylation was increased. ARSB promoter methylation was also increased in cultured metastatic melanoma cells compared to normal melanocytes and to radial growth phase melanoma cells. In the metastatic tissues from skin and liver, SHP2 activity declined, and mRNA expression of MMP2 and CSPG4 increased. When ARSB was silenced By siRNA in the cultured normal melanocytes, Programmed Death-Ligand (PD-L) 1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein By ELISA (p Citation Format: Joanne K. ToBacman, Sumit Bhattacharyya, Leo Feferman. <B>ArylsulfataseB> B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1 [aBstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):ABstract nr B21.
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aBstract 4699 decline in <B>ArylsulfataseB> B arsB increases pd l1 expression in melanoma hepatic prostate and mononuclear cells
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:<B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines and in association with more aggressive prostate cancers. As ARSB decreases, chondroitin 4-sulfate increases, leading to increased Binding of SHP2 (PTP11; non-receptor tyrosine phosphatase) and reduced Binding of galectin-3. SuBsequent effects include increase in phospho-ERK1/2 and transcriptional effects, including hypermethylation of the DKK3 promoter and reduced expression of DKK (Dickkopf WNT pathway signaling inhiBitor) 3, leading to activation of Wnt signaling. Other transcriptional events following silencing of ARSB include: increased expression of CSPG4 and MMP-2 in melanoma cells; increased expression of versican in prostate epithelial cells; increased expression of Wnt9A in colonic epithelial cells; and increased MITF-mediated expression of GPNMB in hepatic cells. Invasiveness of cultured melanoma cells increased when ARSB was silenced By siRNA. To further address the role of ARSB, metastatic melanoma tissue was oBtained from the Biorepository of the University of Illinois at Chicago. Expression of CSPG4 and MMP2 was increased in the metastatic tissues and SHP2 activity was reduced. When ARSB was silenced By siRNA in cultured normal melanocytes (PCS 200-013, ATCC), Programmed Death-Ligand (PD-L)1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein (ELISA assay; p Citation Format: Joanne Kramer ToBacman, Sumit Bhattacharyya, Leo Feferman. Decline in <B>ArylsulfataseB> B (ARSB) increases PD-L1 expression in melanoma, hepatic, prostate, and mononuclear cells [aBstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):ABstract nr 4699.
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aBstract 4698 increased chst15 expression follows declines in <B>ArylsulfataseB> B arsB and dkk3 and disinhiBition of non canonical wnt signaling
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:CHST15 (carBohydrate sulfotransferase 15; chondroitin 4-sulfate-6-sulfotransferase), is the sulfotransferase enzyme which adds 6-sulfate to chondroitin 4-sulfate to make chondroitin 4,6-sulfate, known as CSE. Increased CHST15 expression has Been identified in malignant pancreas, renal, colon, ovary, and prostate tissues. We now report a pathway By which expression of CHST15 is increased following decline in the enzyme ARSB (<B>ArylsulfataseB> B; N-acetylgalactosamine-4-sulfatase), which is required for removal of 4-sulfate groups from chondroitin 4-sulfate (C4S). Previous work has shown that decline in ARSB and the resulting increase in C4S leads to decline in activity of SHP2, a uBiquitous non-receptor tyrosine phosphatase, due to enhanced Binding of SHP2 with C4S when ARSB is reduced. Decline in SHP2 leads to enhanced ERK1/2 phosphorylation and suBsequent downstream effects, including hypermethylation of the DKK (Dickkopf WNT signaling pathway inhiBitor)3 promoter and suppressed DKK3 expression. Since DKK3 acts to inhiBit Wnt signaling, Wnt signaling is enhanced in prostate epithelium when ARSB is reduced. Experiments were performed to identify the pathway By which CHST15 expression is up-regulated when ARSB is reduced and to assess the role of Wnt. The impact of ARSB silencing on CHST15 expression was determined in normal and malignant human prostate cells, in normal and malignant prostate tissue oBtained By laser-capture microdissection, in HepG2 cells, and in prostate tissue of the ARSB-null mouse. Effects of selective inhiBitors of Wnt and MAPK signaling pathways on CHST15 expression were evaluated. CHST15 expression was increased in malignant prostate epithelial tissue, in ARSB-null mouse prostate tissue, and following ARSB silencing in human prostate epithelial cells. The activation of Wnt signaling which followed declines in ARSB and DKK3 was required for increased CHST15 expression. InhiBition of Wnt3A Blocked the increase in CHST15 expression in prostate epithelial cells co-cultured with prostate stromal cells, whereas DKK3 antiBody increased CHST15. InhiBition of Rac-1 GTPase and of phospho-p38 MAPK signaling Blocked the oBserved increase in CHST15 expression, whereas inhiBition of JNK, Sp1, or of Rho kinase had no effect. These results indicate that the increase in epithelial CHST15 occurred in the malignant prostate cells and tissue due to effects of non-canonical Wnt signaling leading to enhanced phospho-p38 MAPK. The resultant increase in CHST15 when ARSB activity is reduced may contriBute to determination of epithelial vs. stromal characteristics. Citation Format: Joanne Kramer ToBacman, Sumit Bhattacharyya, Leo Feferman. Increased CHST15 expression follows declines in <B>ArylsulfataseB> B (ARSB) and DKK3 and disinhiBition of non-canonical WNT signaling [aBstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):ABstract nr 4698.
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decline in <B>ArylsulfataseB> B expression increases egfr expression By inhiBiting the protein tyrosine phosphatase shp2 and activating jnk in prostate cells
2018Co-Authors: Sumit Bhattacharyya, Leo Feferman, Robert J. Linhardt, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Joanne K TobacmanAbstract:Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to Be up-regulated when <B>ArylsulfataseB> B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously Been reported to inhiBit the activity of the uBiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism By which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 Binds preferentially C4S, rather than chondroitin 6-sulfate, and confirm that SHP2 activity declines when ARSB is silenced. The reduction in ARSB activity, and the resultant increase in C4S, increased the expression of EGFR (Her1/ErBB1) in human prostate stem and epithelial cells. The increased expression of EGFR occurred after 1) the decline in SHP2 activity, 2) enhanced c-Jun N-terminal kinase (JNK) activity, 3) increased nuclear DNA Binding By c-Jun and c-Fos, and 4) EGFR promoter activation. In response to exogenous EGF, there was increased Bromodeoxyuridine incorporation, consistent with enhanced cell proliferation. These findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine–tyrosine kinase and the mRNA expression of a critical tyrosine kinase receptor in prostate cells. Restoration of ARSB activity with the associated reduction in C4S may provide a new therapeutic approach for managing malignancies in which EGFR-mediated tyrosine kinase signaling pathways are active.
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increased gpnmB phospho erk1 2 and mmp 9 in cystic fiBrosis in association with reduced <B>ArylsulfataseB> B
2018Co-Authors: Sumit Bhattacharyya, Leo Feferman, Girish Sharma, Joanne K TobacmanAbstract:ABstract Background GPNMB was increased in a CF gene array and in <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fiBrosis (CF). Implications of GPNMB increase in CF are unknown. Methods GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB Binding with β-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR-corrected, and normal human Bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhiBitor. Results GPNMB was markedly increased in CF patients compared to controls (p Conclusions Findings suggest that decline in ARSB activity caused By decline in CFTR function leads to increased GPNMB, which may contriBute to organ dysfunction in CF By increased MMP-9 expression.
Sumit Bhattacharyya - One of the best experts on this subject based on the ideXlab platform.
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aBstract B21 <B>ArylsulfataseB> B arsB is reduced in melanoma metastases and decline in arsB increases programmed death ligand pdl 1
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:<B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines. C4S increased as ARSB declined in the cultured melanoma cell lines. Decline in ARSB was associated with increased expression of chondroitin sulfate proteoglycan (CSPG) 4 and matrix metalloproteinase (MMP) 2. The increase in CSPG4 was attriButed to reduced Binding of galectin-3 with C4S, and the increase of MMP2 was attriButed to inhiBition of SHP2, the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), due to increased Binding with C4S. The invasiveness of the cultured melanoma cells increased when ARSB was silenced By siRNA. To further address the role of ARSB in melanoma progression, metastatic melanoma tissue was oBtained from the Biorepository of the University of Illinois at Chicago. ARSB activity and expression were reduced in the metastatic tissues and ARSB promoter methylation was increased. ARSB promoter methylation was also increased in cultured metastatic melanoma cells compared to normal melanocytes and to radial growth phase melanoma cells. In the metastatic tissues from skin and liver, SHP2 activity declined, and mRNA expression of MMP2 and CSPG4 increased. When ARSB was silenced By siRNA in the cultured normal melanocytes, Programmed Death-Ligand (PD-L) 1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein By ELISA (p Citation Format: Joanne K. ToBacman, Sumit Bhattacharyya, Leo Feferman. <B>ArylsulfataseB> B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1 [aBstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):ABstract nr B21.
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aBstract 4699 decline in <B>ArylsulfataseB> B arsB increases pd l1 expression in melanoma hepatic prostate and mononuclear cells
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:<B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines and in association with more aggressive prostate cancers. As ARSB decreases, chondroitin 4-sulfate increases, leading to increased Binding of SHP2 (PTP11; non-receptor tyrosine phosphatase) and reduced Binding of galectin-3. SuBsequent effects include increase in phospho-ERK1/2 and transcriptional effects, including hypermethylation of the DKK3 promoter and reduced expression of DKK (Dickkopf WNT pathway signaling inhiBitor) 3, leading to activation of Wnt signaling. Other transcriptional events following silencing of ARSB include: increased expression of CSPG4 and MMP-2 in melanoma cells; increased expression of versican in prostate epithelial cells; increased expression of Wnt9A in colonic epithelial cells; and increased MITF-mediated expression of GPNMB in hepatic cells. Invasiveness of cultured melanoma cells increased when ARSB was silenced By siRNA. To further address the role of ARSB, metastatic melanoma tissue was oBtained from the Biorepository of the University of Illinois at Chicago. Expression of CSPG4 and MMP2 was increased in the metastatic tissues and SHP2 activity was reduced. When ARSB was silenced By siRNA in cultured normal melanocytes (PCS 200-013, ATCC), Programmed Death-Ligand (PD-L)1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein (ELISA assay; p Citation Format: Joanne Kramer ToBacman, Sumit Bhattacharyya, Leo Feferman. Decline in <B>ArylsulfataseB> B (ARSB) increases PD-L1 expression in melanoma, hepatic, prostate, and mononuclear cells [aBstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):ABstract nr 4699.
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aBstract 4698 increased chst15 expression follows declines in <B>ArylsulfataseB> B arsB and dkk3 and disinhiBition of non canonical wnt signaling
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:CHST15 (carBohydrate sulfotransferase 15; chondroitin 4-sulfate-6-sulfotransferase), is the sulfotransferase enzyme which adds 6-sulfate to chondroitin 4-sulfate to make chondroitin 4,6-sulfate, known as CSE. Increased CHST15 expression has Been identified in malignant pancreas, renal, colon, ovary, and prostate tissues. We now report a pathway By which expression of CHST15 is increased following decline in the enzyme ARSB (<B>ArylsulfataseB> B; N-acetylgalactosamine-4-sulfatase), which is required for removal of 4-sulfate groups from chondroitin 4-sulfate (C4S). Previous work has shown that decline in ARSB and the resulting increase in C4S leads to decline in activity of SHP2, a uBiquitous non-receptor tyrosine phosphatase, due to enhanced Binding of SHP2 with C4S when ARSB is reduced. Decline in SHP2 leads to enhanced ERK1/2 phosphorylation and suBsequent downstream effects, including hypermethylation of the DKK (Dickkopf WNT signaling pathway inhiBitor)3 promoter and suppressed DKK3 expression. Since DKK3 acts to inhiBit Wnt signaling, Wnt signaling is enhanced in prostate epithelium when ARSB is reduced. Experiments were performed to identify the pathway By which CHST15 expression is up-regulated when ARSB is reduced and to assess the role of Wnt. The impact of ARSB silencing on CHST15 expression was determined in normal and malignant human prostate cells, in normal and malignant prostate tissue oBtained By laser-capture microdissection, in HepG2 cells, and in prostate tissue of the ARSB-null mouse. Effects of selective inhiBitors of Wnt and MAPK signaling pathways on CHST15 expression were evaluated. CHST15 expression was increased in malignant prostate epithelial tissue, in ARSB-null mouse prostate tissue, and following ARSB silencing in human prostate epithelial cells. The activation of Wnt signaling which followed declines in ARSB and DKK3 was required for increased CHST15 expression. InhiBition of Wnt3A Blocked the increase in CHST15 expression in prostate epithelial cells co-cultured with prostate stromal cells, whereas DKK3 antiBody increased CHST15. InhiBition of Rac-1 GTPase and of phospho-p38 MAPK signaling Blocked the oBserved increase in CHST15 expression, whereas inhiBition of JNK, Sp1, or of Rho kinase had no effect. These results indicate that the increase in epithelial CHST15 occurred in the malignant prostate cells and tissue due to effects of non-canonical Wnt signaling leading to enhanced phospho-p38 MAPK. The resultant increase in CHST15 when ARSB activity is reduced may contriBute to determination of epithelial vs. stromal characteristics. Citation Format: Joanne Kramer ToBacman, Sumit Bhattacharyya, Leo Feferman. Increased CHST15 expression follows declines in <B>ArylsulfataseB> B (ARSB) and DKK3 and disinhiBition of non-canonical WNT signaling [aBstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):ABstract nr 4698.
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decline in <B>ArylsulfataseB> B expression increases egfr expression By inhiBiting the protein tyrosine phosphatase shp2 and activating jnk in prostate cells
2018Co-Authors: Sumit Bhattacharyya, Leo Feferman, Robert J. Linhardt, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Joanne K TobacmanAbstract:Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to Be up-regulated when <B>ArylsulfataseB> B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously Been reported to inhiBit the activity of the uBiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism By which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 Binds preferentially C4S, rather than chondroitin 6-sulfate, and confirm that SHP2 activity declines when ARSB is silenced. The reduction in ARSB activity, and the resultant increase in C4S, increased the expression of EGFR (Her1/ErBB1) in human prostate stem and epithelial cells. The increased expression of EGFR occurred after 1) the decline in SHP2 activity, 2) enhanced c-Jun N-terminal kinase (JNK) activity, 3) increased nuclear DNA Binding By c-Jun and c-Fos, and 4) EGFR promoter activation. In response to exogenous EGF, there was increased Bromodeoxyuridine incorporation, consistent with enhanced cell proliferation. These findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine–tyrosine kinase and the mRNA expression of a critical tyrosine kinase receptor in prostate cells. Restoration of ARSB activity with the associated reduction in C4S may provide a new therapeutic approach for managing malignancies in which EGFR-mediated tyrosine kinase signaling pathways are active.
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increased gpnmB phospho erk1 2 and mmp 9 in cystic fiBrosis in association with reduced <B>ArylsulfataseB> B
2018Co-Authors: Sumit Bhattacharyya, Leo Feferman, Girish Sharma, Joanne K TobacmanAbstract:ABstract Background GPNMB was increased in a CF gene array and in <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fiBrosis (CF). Implications of GPNMB increase in CF are unknown. Methods GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB Binding with β-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR-corrected, and normal human Bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhiBitor. Results GPNMB was markedly increased in CF patients compared to controls (p Conclusions Findings suggest that decline in ARSB activity caused By decline in CFTR function leads to increased GPNMB, which may contriBute to organ dysfunction in CF By increased MMP-9 expression.
Leo Feferman - One of the best experts on this subject based on the ideXlab platform.
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aBstract B21 <B>ArylsulfataseB> B arsB is reduced in melanoma metastases and decline in arsB increases programmed death ligand pdl 1
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:<B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines. C4S increased as ARSB declined in the cultured melanoma cell lines. Decline in ARSB was associated with increased expression of chondroitin sulfate proteoglycan (CSPG) 4 and matrix metalloproteinase (MMP) 2. The increase in CSPG4 was attriButed to reduced Binding of galectin-3 with C4S, and the increase of MMP2 was attriButed to inhiBition of SHP2, the tyrosine-protein phosphatase nonreceptor type 11 (PTPN11), due to increased Binding with C4S. The invasiveness of the cultured melanoma cells increased when ARSB was silenced By siRNA. To further address the role of ARSB in melanoma progression, metastatic melanoma tissue was oBtained from the Biorepository of the University of Illinois at Chicago. ARSB activity and expression were reduced in the metastatic tissues and ARSB promoter methylation was increased. ARSB promoter methylation was also increased in cultured metastatic melanoma cells compared to normal melanocytes and to radial growth phase melanoma cells. In the metastatic tissues from skin and liver, SHP2 activity declined, and mRNA expression of MMP2 and CSPG4 increased. When ARSB was silenced By siRNA in the cultured normal melanocytes, Programmed Death-Ligand (PD-L) 1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein By ELISA (p Citation Format: Joanne K. ToBacman, Sumit Bhattacharyya, Leo Feferman. <B>ArylsulfataseB> B (ARSB) is reduced in melanoma metastases and decline in ARSB increases programmed death-ligand (PDL) 1 [aBstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):ABstract nr B21.
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aBstract 4699 decline in <B>ArylsulfataseB> B arsB increases pd l1 expression in melanoma hepatic prostate and mononuclear cells
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:<B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase) is the enzyme that removes 4-sulfate groups from chondroitin 4-sulfate (C4S) and dermatan sulfate. In previous work, we have shown decline in ARSB with increasing aggressiveness of melanoma cell lines and in association with more aggressive prostate cancers. As ARSB decreases, chondroitin 4-sulfate increases, leading to increased Binding of SHP2 (PTP11; non-receptor tyrosine phosphatase) and reduced Binding of galectin-3. SuBsequent effects include increase in phospho-ERK1/2 and transcriptional effects, including hypermethylation of the DKK3 promoter and reduced expression of DKK (Dickkopf WNT pathway signaling inhiBitor) 3, leading to activation of Wnt signaling. Other transcriptional events following silencing of ARSB include: increased expression of CSPG4 and MMP-2 in melanoma cells; increased expression of versican in prostate epithelial cells; increased expression of Wnt9A in colonic epithelial cells; and increased MITF-mediated expression of GPNMB in hepatic cells. Invasiveness of cultured melanoma cells increased when ARSB was silenced By siRNA. To further address the role of ARSB, metastatic melanoma tissue was oBtained from the Biorepository of the University of Illinois at Chicago. Expression of CSPG4 and MMP2 was increased in the metastatic tissues and SHP2 activity was reduced. When ARSB was silenced By siRNA in cultured normal melanocytes (PCS 200-013, ATCC), Programmed Death-Ligand (PD-L)1 increased from 78 ± 7 pg/mg protein to 128 ± 11 pg/mg protein (ELISA assay; p Citation Format: Joanne Kramer ToBacman, Sumit Bhattacharyya, Leo Feferman. Decline in <B>ArylsulfataseB> B (ARSB) increases PD-L1 expression in melanoma, hepatic, prostate, and mononuclear cells [aBstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):ABstract nr 4699.
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aBstract 4698 increased chst15 expression follows declines in <B>ArylsulfataseB> B arsB and dkk3 and disinhiBition of non canonical wnt signaling
2020Co-Authors: Joanne K Tobacman, Sumit Bhattacharyya, Leo FefermanAbstract:CHST15 (carBohydrate sulfotransferase 15; chondroitin 4-sulfate-6-sulfotransferase), is the sulfotransferase enzyme which adds 6-sulfate to chondroitin 4-sulfate to make chondroitin 4,6-sulfate, known as CSE. Increased CHST15 expression has Been identified in malignant pancreas, renal, colon, ovary, and prostate tissues. We now report a pathway By which expression of CHST15 is increased following decline in the enzyme ARSB (<B>ArylsulfataseB> B; N-acetylgalactosamine-4-sulfatase), which is required for removal of 4-sulfate groups from chondroitin 4-sulfate (C4S). Previous work has shown that decline in ARSB and the resulting increase in C4S leads to decline in activity of SHP2, a uBiquitous non-receptor tyrosine phosphatase, due to enhanced Binding of SHP2 with C4S when ARSB is reduced. Decline in SHP2 leads to enhanced ERK1/2 phosphorylation and suBsequent downstream effects, including hypermethylation of the DKK (Dickkopf WNT signaling pathway inhiBitor)3 promoter and suppressed DKK3 expression. Since DKK3 acts to inhiBit Wnt signaling, Wnt signaling is enhanced in prostate epithelium when ARSB is reduced. Experiments were performed to identify the pathway By which CHST15 expression is up-regulated when ARSB is reduced and to assess the role of Wnt. The impact of ARSB silencing on CHST15 expression was determined in normal and malignant human prostate cells, in normal and malignant prostate tissue oBtained By laser-capture microdissection, in HepG2 cells, and in prostate tissue of the ARSB-null mouse. Effects of selective inhiBitors of Wnt and MAPK signaling pathways on CHST15 expression were evaluated. CHST15 expression was increased in malignant prostate epithelial tissue, in ARSB-null mouse prostate tissue, and following ARSB silencing in human prostate epithelial cells. The activation of Wnt signaling which followed declines in ARSB and DKK3 was required for increased CHST15 expression. InhiBition of Wnt3A Blocked the increase in CHST15 expression in prostate epithelial cells co-cultured with prostate stromal cells, whereas DKK3 antiBody increased CHST15. InhiBition of Rac-1 GTPase and of phospho-p38 MAPK signaling Blocked the oBserved increase in CHST15 expression, whereas inhiBition of JNK, Sp1, or of Rho kinase had no effect. These results indicate that the increase in epithelial CHST15 occurred in the malignant prostate cells and tissue due to effects of non-canonical Wnt signaling leading to enhanced phospho-p38 MAPK. The resultant increase in CHST15 when ARSB activity is reduced may contriBute to determination of epithelial vs. stromal characteristics. Citation Format: Joanne Kramer ToBacman, Sumit Bhattacharyya, Leo Feferman. Increased CHST15 expression follows declines in <B>ArylsulfataseB> B (ARSB) and DKK3 and disinhiBition of non-canonical WNT signaling [aBstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):ABstract nr 4698.
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decline in <B>ArylsulfataseB> B expression increases egfr expression By inhiBiting the protein tyrosine phosphatase shp2 and activating jnk in prostate cells
2018Co-Authors: Sumit Bhattacharyya, Leo Feferman, Robert J. Linhardt, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Joanne K TobacmanAbstract:Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to Be up-regulated when <B>ArylsulfataseB> B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously Been reported to inhiBit the activity of the uBiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism By which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 Binds preferentially C4S, rather than chondroitin 6-sulfate, and confirm that SHP2 activity declines when ARSB is silenced. The reduction in ARSB activity, and the resultant increase in C4S, increased the expression of EGFR (Her1/ErBB1) in human prostate stem and epithelial cells. The increased expression of EGFR occurred after 1) the decline in SHP2 activity, 2) enhanced c-Jun N-terminal kinase (JNK) activity, 3) increased nuclear DNA Binding By c-Jun and c-Fos, and 4) EGFR promoter activation. In response to exogenous EGF, there was increased Bromodeoxyuridine incorporation, consistent with enhanced cell proliferation. These findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine–tyrosine kinase and the mRNA expression of a critical tyrosine kinase receptor in prostate cells. Restoration of ARSB activity with the associated reduction in C4S may provide a new therapeutic approach for managing malignancies in which EGFR-mediated tyrosine kinase signaling pathways are active.
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increased gpnmB phospho erk1 2 and mmp 9 in cystic fiBrosis in association with reduced <B>ArylsulfataseB> B
2018Co-Authors: Sumit Bhattacharyya, Leo Feferman, Girish Sharma, Joanne K TobacmanAbstract:ABstract Background GPNMB was increased in a CF gene array and in <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fiBrosis (CF). Implications of GPNMB increase in CF are unknown. Methods GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB Binding with β-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR-corrected, and normal human Bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhiBitor. Results GPNMB was markedly increased in CF patients compared to controls (p Conclusions Findings suggest that decline in ARSB activity caused By decline in CFTR function leads to increased GPNMB, which may contriBute to organ dysfunction in CF By increased MMP-9 expression.
Marina Guizzetti - One of the best experts on this subject based on the ideXlab platform.
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decline in <B>ArylsulfataseB> B and increase in chondroitin 4 sulfotransferase comBine to increase chondroitin 4 sulfate in traumatic Brain injury
2015Co-Authors: Sumit Bhattacharyya, Leo Feferman, Marina Guizzetti, Frank C Tortella, Xiaolu Zhang, David Johnson, Joanne K TobacmanAbstract:In an estaBlished rat model of penetrating Ballistic-like Brain injury (PBBI), <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, But unaffected at the contralateral site or in sham controls. In addition, the ARSB suBstrate chondroitin 4-sulfate (C4S) and total sulfated glycosaminoglycans increased. The mRNA expression of chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contriButions from Both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia induciBle factor (HIF)-1α increased significantly. In contrast, sulfotransferase activity and chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, But not following scratch. These different pathways By which C4S increased in the cell preparations were Both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury due to mechanical disruption inhiBiting ARSB and to chemical mediation By TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following TBI is due to contriButions from impaired degradation and enhanced synthesis of C4S which comBine in the pathogenesis of the glial scar.
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decline in <B>ArylsulfataseB> B and increase in chondroitin 4 sulfotransferase comBine to increase chondroitin 4 sulfate in traumatic Brain injury
2015Co-Authors: Leo Feferman, Marina Guizzetti, Frank C Tortella, Xiaolu Zhang, Sumit Bhattacharyya, David Johnson, Joanne K TobacmanAbstract:In an estaBlished rat model of penetrating Ballistic-like Brain injury (PBBI), <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, But unaffected at the contralateral site or in sham controls. In addition, the ARSB suBstrate chondroitin 4-sulfate (C4S) and total sulfated glycosaminoglycans increased. The mRNA expression of chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contriButions from Both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia induciBle factor-1α increased significantly. In contrast, sulfotransferase activity and chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, But not following scratch. These different pathways By which C4S increased in the cell preparations were Both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury Because of mechanical disruption inhiBiting ARSB and to chemical mediation By TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following traumatic Brain injury is Because of contriButions from impaired degradation and enhanced synthesis of C4S which comBine in the pathogenesis of the glial scar. This is the first report of how two mechanisms contriBute to the increase in chondroitin 4-sulfate (C4S) in TBI. Following penetrating Ballistic-like Brain injury in a rat model and in the scratch model of injury in fetal rat astrocytes, <B>ArylsulfataseB> B activity declined, leading to accumulation of C4S. TGF-β1 exposure increased expression of chondroitin 4-sulfotransferase. Hence, the increase in C4S in TBI is attriButaBle to Both impaired degradation and enhanced synthesis, comBining in the pathogenesis of the glial scar.
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<B>ArylsulfataseB> B modulates neurite outgrowth via astrocyte chondroitin 4 sulfate dysregulation By ethanol
2014Co-Authors: Xiaolu Zhang, Marina Guizzetti, Sumit Bhattacharyya, Joanne K Tobacman, Handojo Kusumo, Charles R GoodlettAbstract:In utero ethanol exposure causes Fetal Alcohol Spectrum Disorders, associated with reduced Brain plasticity; the mechanisms of these effects are not well understood, particularly with respect to glial involvement. Astrocytes release factors that modulate neurite outgrowth. We explored the hypothesis that ethanol inhiBits neurite outgrowth By increasing the release of inhiBitory chondroitin sulfate proteoglycans (CSPGs) from astrocytes. Astrocyte treatment with ethanol inhiBited the activity of <B>ArylsulfataseB> B (ARSB), the enzyme that removes sulfate groups from chondroitin-4-sulfate (C4S) and triggers the degradation of C4S, increased total sulfated glycosaminoglycans (GAGs), C4S, and neurocan core-protein content and inhiBited neurite outgrowth in neurons co-cultured with ethanol-treated astrocytes in vitro, effects reversed By treatment with recomBinant ARSB. Ethanol also inhiBited ARSB activity and increased sulfate GAG and neurocan levels in the developing hippocampus after in vivo ethanol exposure. ARSB silencing increased the levels of sulfated GAGs, C4S, and neurocan in astrocytes and inhiBited neurite outgrowth in co-cultured neurons, indicating that ARSB activity directly regulates C4S and affects neurocan expression. In summary, this study reports two major findings: ARSB modulates sulfated GAG and neurocan levels in astrocytes and astrocyte-mediated neurite outgrowth in co-cultured neurons; and ethanol inhiBits the activity of ARSB, increases sulfated GAG, C4S, and neurocan levels, and thereBy inhiBits astrocyte-mediated neurite outgrowth. An unscheduled increase in CSPGs in the developing Brain may lead to altered Brain connectivity and to premature decrease in neuronal plasticity and therefore represents a novel mechanism By which ethanol can exert its neurodevelopmental effects.
Xiaolu Zhang - One of the best experts on this subject based on the ideXlab platform.
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decline in <B>ArylsulfataseB> B and increase in chondroitin 4 sulfotransferase comBine to increase chondroitin 4 sulfate in traumatic Brain injury
2015Co-Authors: Sumit Bhattacharyya, Leo Feferman, Marina Guizzetti, Frank C Tortella, Xiaolu Zhang, David Johnson, Joanne K TobacmanAbstract:In an estaBlished rat model of penetrating Ballistic-like Brain injury (PBBI), <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, But unaffected at the contralateral site or in sham controls. In addition, the ARSB suBstrate chondroitin 4-sulfate (C4S) and total sulfated glycosaminoglycans increased. The mRNA expression of chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contriButions from Both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia induciBle factor (HIF)-1α increased significantly. In contrast, sulfotransferase activity and chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, But not following scratch. These different pathways By which C4S increased in the cell preparations were Both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury due to mechanical disruption inhiBiting ARSB and to chemical mediation By TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following TBI is due to contriButions from impaired degradation and enhanced synthesis of C4S which comBine in the pathogenesis of the glial scar.
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decline in <B>ArylsulfataseB> B and increase in chondroitin 4 sulfotransferase comBine to increase chondroitin 4 sulfate in traumatic Brain injury
2015Co-Authors: Leo Feferman, Marina Guizzetti, Frank C Tortella, Xiaolu Zhang, Sumit Bhattacharyya, David Johnson, Joanne K TobacmanAbstract:In an estaBlished rat model of penetrating Ballistic-like Brain injury (PBBI), <B>ArylsulfataseB> B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, But unaffected at the contralateral site or in sham controls. In addition, the ARSB suBstrate chondroitin 4-sulfate (C4S) and total sulfated glycosaminoglycans increased. The mRNA expression of chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contriButions from Both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia induciBle factor-1α increased significantly. In contrast, sulfotransferase activity and chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, But not following scratch. These different pathways By which C4S increased in the cell preparations were Both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury Because of mechanical disruption inhiBiting ARSB and to chemical mediation By TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following traumatic Brain injury is Because of contriButions from impaired degradation and enhanced synthesis of C4S which comBine in the pathogenesis of the glial scar. This is the first report of how two mechanisms contriBute to the increase in chondroitin 4-sulfate (C4S) in TBI. Following penetrating Ballistic-like Brain injury in a rat model and in the scratch model of injury in fetal rat astrocytes, <B>ArylsulfataseB> B activity declined, leading to accumulation of C4S. TGF-β1 exposure increased expression of chondroitin 4-sulfotransferase. Hence, the increase in C4S in TBI is attriButaBle to Both impaired degradation and enhanced synthesis, comBining in the pathogenesis of the glial scar.
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<B>ArylsulfataseB> B modulates neurite outgrowth via astrocyte chondroitin 4 sulfate dysregulation By ethanol
2014Co-Authors: Xiaolu Zhang, Marina Guizzetti, Sumit Bhattacharyya, Joanne K Tobacman, Handojo Kusumo, Charles R GoodlettAbstract:In utero ethanol exposure causes Fetal Alcohol Spectrum Disorders, associated with reduced Brain plasticity; the mechanisms of these effects are not well understood, particularly with respect to glial involvement. Astrocytes release factors that modulate neurite outgrowth. We explored the hypothesis that ethanol inhiBits neurite outgrowth By increasing the release of inhiBitory chondroitin sulfate proteoglycans (CSPGs) from astrocytes. Astrocyte treatment with ethanol inhiBited the activity of <B>ArylsulfataseB> B (ARSB), the enzyme that removes sulfate groups from chondroitin-4-sulfate (C4S) and triggers the degradation of C4S, increased total sulfated glycosaminoglycans (GAGs), C4S, and neurocan core-protein content and inhiBited neurite outgrowth in neurons co-cultured with ethanol-treated astrocytes in vitro, effects reversed By treatment with recomBinant ARSB. Ethanol also inhiBited ARSB activity and increased sulfate GAG and neurocan levels in the developing hippocampus after in vivo ethanol exposure. ARSB silencing increased the levels of sulfated GAGs, C4S, and neurocan in astrocytes and inhiBited neurite outgrowth in co-cultured neurons, indicating that ARSB activity directly regulates C4S and affects neurocan expression. In summary, this study reports two major findings: ARSB modulates sulfated GAG and neurocan levels in astrocytes and astrocyte-mediated neurite outgrowth in co-cultured neurons; and ethanol inhiBits the activity of ARSB, increases sulfated GAG, C4S, and neurocan levels, and thereBy inhiBits astrocyte-mediated neurite outgrowth. An unscheduled increase in CSPGs in the developing Brain may lead to altered Brain connectivity and to premature decrease in neuronal plasticity and therefore represents a novel mechanism By which ethanol can exert its neurodevelopmental effects.
