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AKAP12

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Irwin H Gelman – 1st expert on this subject based on the ideXlab platform

  • SSeCKS/AKAP12 suppresses metastatic melanoma lung colonization by attenuating Src-mediated pre-metastatic niche crosstalk.
    Oncotarget, 2018
    Co-Authors: Masashi Muramatsu, Shin Akakura, Jennifer Peresie, Benjamin Balderman, Irwin H Gelman

    Abstract:

    // Masashi Muramatsu 1 , Shin Akakura 2 , Lingqiu Gao 3 , Jennifer Peresie 3 , Benjamin Balderman 3 and Irwin H. Gelman 3 1 Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan 2 Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine 92618, CA, USA 3 Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo 14263, NY, USA Correspondence to: Irwin H. Gelman, email: Irwin.gelman@roswellpark.org Keywords: SSeCKS/AKAP12; pre-metastatic niche; melanoma; lung endothelial cells; adhesion Received: July 25, 2018      Accepted: August 20, 2018      Published: September 11, 2018 ABSTRACT SSeCKS/Gravin/AKAP12 (SSeCKS) controls metastasis-associated PKC and Src signaling through direct scaffolding activity. SSeCKS is downregulated in the metastases of many human cancer types, and its forced re-expression suppresses the metastatic behavior of prostate cancer cells. SSeCKS is also downregulated in breast and prostate cancer stroma, and SSeCKS-null mice (KO) are metastasis-prone, suggesting a role in suppressing formation of the pre-metastatic niche. Here, we show that lung colonization and metastasis formation by B16F10 and SM1WT1[ Braf V600E ] mouse melanoma cells is 9-fold higher in syngeneic KO compared to WT hosts, although there is no difference in orthotopic tumor volumes. Although melanoma cells adhered equally to KO or WT lung fibroblasts (LF), co-injection of melanoma cells with KO (vs. WT) LF increased lung macrometastasis formation in WT hosts, marked by increased melanoma colonization at foci of leaky vasculature. Increased melanoma adhesion on KO lung endothelial cells (LEC) was facilitated by increased E-Selectin levels and by increased STAT3-regulated secretion of senescence-associated factors from KO-LF, such as Vegf. Finally, the ability of SSeCKS to attenuate IFNα-induced Stat3 activation in KO-LF required its Src-scaffolding domain. Taken together, these data suggest that SSeCKS normally suppresses metastatic colonization in the lung by attenuating the expression of Selectin adhesion proteins, which can be controlled autonomously by local endothelial cells or enhanced by senescence factors secreted by neighboring fibroblasts in a SSeCKS-regulated, Src/Stat3-dependent manner.

  • ssecks AKAP12 suppresses metastatic melanoma lung colonization by attenuating src mediated pre metastatic niche crosstalk
    Oncotarget, 2018
    Co-Authors: Masashi Muramatsu, Shin Akakura, Jennifer Peresie, Benjamin Balderman, Irwin H Gelman

    Abstract:

    // Masashi Muramatsu 1 , Shin Akakura 2 , Lingqiu Gao 3 , Jennifer Peresie 3 , Benjamin Balderman 3 and Irwin H. Gelman 3 1 Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan 2 Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine 92618, CA, USA 3 Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo 14263, NY, USA Correspondence to: Irwin H. Gelman, email: Irwin.gelman@roswellpark.org Keywords: SSeCKS/AKAP12; pre-metastatic niche; melanoma; lung endothelial cells; adhesion Received: July 25, 2018      Accepted: August 20, 2018      Published: September 11, 2018 ABSTRACT SSeCKS/Gravin/AKAP12 (SSeCKS) controls metastasis-associated PKC and Src signaling through direct scaffolding activity. SSeCKS is downregulated in the metastases of many human cancer types, and its forced re-expression suppresses the metastatic behavior of prostate cancer cells. SSeCKS is also downregulated in breast and prostate cancer stroma, and SSeCKS-null mice (KO) are metastasis-prone, suggesting a role in suppressing formation of the pre-metastatic niche. Here, we show that lung colonization and metastasis formation by B16F10 and SM1WT1[ Braf V600E ] mouse melanoma cells is 9-fold higher in syngeneic KO compared to WT hosts, although there is no difference in orthotopic tumor volumes. Although melanoma cells adhered equally to KO or WT lung fibroblasts (LF), co-injection of melanoma cells with KO (vs. WT) LF increased lung macrometastasis formation in WT hosts, marked by increased melanoma colonization at foci of leaky vasculature. Increased melanoma adhesion on KO lung endothelial cells (LEC) was facilitated by increased E-Selectin levels and by increased STAT3-regulated secretion of senescence-associated factors from KO-LF, such as Vegf. Finally, the ability of SSeCKS to attenuate IFNα-induced Stat3 activation in KO-LF required its Src-scaffolding domain. Taken together, these data suggest that SSeCKS normally suppresses metastatic colonization in the lung by attenuating the expression of Selectin adhesion proteins, which can be controlled autonomously by local endothelial cells or enhanced by senescence factors secreted by neighboring fibroblasts in a SSeCKS-regulated, Src/Stat3-dependent manner.

  • SSeCKS/AKAP12 scaffolding functions suppress B16F10-induced peritoneal metastasis by attenuating CXCL9/10 secretion by resident fibroblasts
    Oncotarget, 2017
    Co-Authors: Masashi Muramatsu, Shin Akakura, Jennifer Peresie, Benjamin Balderman, Irwin H Gelman

    Abstract:

    // Masashi Muramatsu 1 , Lingqiu Gao 2 , Jennifer Peresie 2 , Benjamin Balderman 2 , Shin Akakura 3 and Irwin H. Gelman 2 1 Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan 2 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo 14263, NY, USA 3 Frontiers in Bioscience Research Institute in Aging and Cancer, Irvine 92618, CA, USA Correspondence to: Irwin H. Gelman, email: Irwin.gelman@roswellpark.org Keywords: SSeCKS/AKAP12, metastasis, senescent secretome, CXCL9/10, CXCR3 Received: June 09, 2017      Accepted: July 26, 2017      Published: August 09, 2017 ABSTRACT SSeCKS/Gravin/AKAP12 (SSeCKS) is a kinase scaffolding protein known to suppress metastasis by attenuating tumor-intrinsic PKC- and Src-mediated signaling pathways [ 1 ]. In addition to downregulation in metastatic cells, in silico analyses identified SSeCKS downregulation in prostate or breast cancer-derived stroma, suggesting a microenvironmental cell role in controlling malignancy. Although orthotopic B16F10 and SM1WT1[ Braf V600E ] mouse melanoma tumors grew similarly in syngeneic WT or SSeCKS-null (KO) mice, KO hosts exhibited 5- to 10-fold higher levels of peritoneal metastasis, and this enhancement could be adoptively transferred by pre-injecting naive WT mice with peritoneal fluid (PF), but not non-adherent peritoneal cells (PC), from naive KO mice. B16F10 and SM1WT1 cells showed increased chemotaxis to KO-PF compared to WT-PF, corresponding to increased PF levels of multiple inflammatory mediators, including the Cxcr3 ligands, Cxcl9 and 10. Cxcr3 knockdown abrogated enhanced chemotaxis to KO-PF and peritoneal metastasis in KO hosts. Conditioned media from KO peritoneal membrane fibroblasts (PMF), but not from KO-PC, induced increased B16F10 chemotaxis over controls, which could be blocked with Cxcl10 neutralizing antibody. KO-PMF exhibited increased levels of the senescence markers, SA-β-galactosidase, p21 waf1 and p16 ink4a , and enhanced Cxcl10 secretion induced by inflammatory mediators, lipopolysaccharide, TNFα, IFNα and IFNγ. SSeCKS scaffolding-site mutants and small molecule kinase inhibitors were used to show that the loss of SSeCKS-regulated PKC, PKA and PI3K/Akt pathways are responsible for the enhanced Cxcl10 secretion. These data mark the first description of a role for stromal SSeCKS/AKAP12 in suppressing metastasis, specifically by attenuating signaling pathways that promote secretion of tumor chemoattractants in the peritoneum.

Bing Su – 2nd expert on this subject based on the ideXlab platform

  • ssecks AKAP12 induces repulsion between human prostate cancer and microvessel endothelial cells through the activation of semaphorin 3f
    Biochemical and Biophysical Research Communications, 2017
    Co-Authors: Wei Su, Lijuan Zhang, Qingkun Shang, Bing Su

    Abstract:

    Abstract Metastasis remains the primary cause of prostate cancer related death. Cancer cells need to contact endothelial cells and disrupt endothelial junctions to cross the endothelium for invasion and metastasis. The suppression of heterotypic repulsion between cancer and endothelial cells allows cancer cells to invade into the surrounding tissue. Here, we demonstrate that SSeCKS/AKAP12 induced repulsion between human prostate cancer and microvessel endothelial cells, which was mediated by an angiogenesis inhibitor Semaphorin 3F. Moreover, we examined AKAP12 and Semaphorin 3F mRNA expression in 42 prostate cancer and 30 benign prostatic hyperplasia tissue samples, and found that the expression of AKAP12 and Semaphorin 3F mRNA was inversely associated with the degree of aggressiveness of prostate cancer cells and tissues. An ordinal logistic regression analysis indicates that there is a positive association between the expression of AKAP12 and Semaphorin 3F in prostate cancer, suggesting that the activation of Semaphorin 3F by SSeCKS/AKAP12 may be involved in prostate cancer progression and metastasis.

  • SSeCKS/AKAP12 induces repulsion between human prostate cancer and microvessel endothelial cells through the activation of Semaphorin 3F
    Biochemical and Biophysical Research Communications, 2017
    Co-Authors: Wei Su, Lijuan Zhang, Qingkun Shang, Bing Su

    Abstract:

    Abstract Metastasis remains the primary cause of prostate cancer related death. Cancer cells need to contact endothelial cells and disrupt endothelial junctions to cross the endothelium for invasion and metastasis. The suppression of heterotypic repulsion between cancer and endothelial cells allows cancer cells to invade into the surrounding tissue. Here, we demonstrate that SSeCKS/AKAP12 induced repulsion between human prostate cancer and microvessel endothelial cells, which was mediated by an angiogenesis inhibitor Semaphorin 3F. Moreover, we examined AKAP12 and Semaphorin 3F mRNA expression in 42 prostate cancer and 30 benign prostatic hyperplasia tissue samples, and found that the expression of AKAP12 and Semaphorin 3F mRNA was inversely associated with the degree of aggressiveness of prostate cancer cells and tissues. An ordinal logistic regression analysis indicates that there is a positive association between the expression of AKAP12 and Semaphorin 3F in prostate cancer, suggesting that the activation of Semaphorin 3F by SSeCKS/AKAP12 may be involved in prostate cancer progression and metastasis.

  • rapid determination of AKAP12 promoter methylation levels in peripheral blood using methylation sensitive high resolution melting ms hrm analysis application in colorectal cancer
    Clinica Chimica Acta, 2010
    Co-Authors: Ming Guan, Bing Su, Ji Li, Min Li, Yuan Lu

    Abstract:

    Abstract Background Colorectal cancer is the third most common form of cancer and hypermethylation has been shown to increase the risk of developing this disease. DNA hypermethylation in the A kinase anchor protein 12 (AKAP12/Gravin) promoter region and the accompanied underexpression of it has been noted in a variety of human cancers. Methods We applied methylation-specific high resolution melting (MS-HRM) technology to detect quantitatively A kinase anchor protein 12 (AKAP12/Gravin) methylation in peripheral blood from 100 colorectal cancer patients and 50 healthy volunteers and in 3 colorectal cancer cell lines. Results In this study 48 of the 100 colorectal cancer samples (48%) were found to be methylated at the AKAP12 promoter region. AKAP12 methylation was significantly higher in the colorectal cancer samples with differentiation (p = 0.03). We also compared the results generated by MS-HRM with a traditional methylation-specific PCR (MSP) assay. We found that intra-assay variability ranged from 6.14 to 9.90% and inter-assay variability ranged from 14.5 to 17.2%. The AKAP12 MS-HRM assay was able to reproducibly detect 1% methylated DNA, whereas the MSP method was unable to detect less than 5% methylation. Conclusions We demonstrate the utility of quantitative AKAP12 MS-HRM analysis of promoter methylation in peripheral blood samples. AKAP12 MS-HRM quantitative methods with excellent detection capabilities have many promising applications in the research and diagnosis of colorectal cancer.

Yuan Lu – 3rd expert on this subject based on the ideXlab platform

  • re expression of AKAP12 inhibits progression and metastasis potential of colorectal carcinoma in vivo and in vitro
    PLOS ONE, 2011
    Co-Authors: Ming Guan, Tingting Hu, Xiaoye Gu, Yuan Lu

    Abstract:

    Background: AKAP12/Gravin (A kinase anchor protein 12) is one of the A-kinase scaffold proteins and a potential tumor suppressor gene in human primary cancers. Our recent study demonstrated the highly recurrent loss of AKAP12 in colorectal cancer and AKAP12 reexpression inhibited proliferation and anchorage-independent growth in colorectal cancer cells, implicating AKAP12 in colorectal cancer pathogenesis. Methods: To evaluate the effect of this gene on the progression and metastasis of colorectal cancer, we examined the impact of overexpressing AKAP12 in the AKAP12-negative human colorectal cancer cell line LoVo, the single clone (LoVoAKAP12) compared to mock-transfected cells (LoVo-CON). Results: pCMV6-AKAP12-mediated AKAP12 re-expression induced apoptosis (3% to 12.7%, p,0.01), migration (89.667.5 cells to 31.064.1 cells, p,0.01) and invasion (82.765.2 cells to 24.763.3 cells, p,0.01) of LoVo cells in vitro compared to control cells. Nude mice injected with LoVo-AKAP12 cells had both significantly reduced tumor volume (p,0.01) and increased apoptosis compared to mice given AKAP12-CON. The quantitative human-specific Alu PCR analysis showed overexpression of AKAP12 suppressed the number of intravasated cells in vivo (p,0.01). Conclusion: These results demonstrate that AKAP12 may play an important role in tumor growth suppression and the survival of human colorectal cancer.

  • quantitative assessment of AKAP12 promoter methylation in human prostate cancer using methylation sensitive high resolution melting correlation with gleason score
    Urology, 2011
    Co-Authors: Jian Gong, Ming Guan, Tingting Hu, Jinghui Hu, Junhua Du, Haowen Jiang, Yuan Lu

    Abstract:

    Objectives To quantitatively investigate the A kinase anchoring protein 12 ( AKAP12 ) gene promoter methylation and its association with clinicopathologic variables in human prostate cancer (PCa). The AKAP12 gene has shown reduced expression and marked hypermethylation in a variety of cancers. Methods The percentage levels of DNA methylation were measured in 78 PCa, 22 benign prostatic hyperplasia, and 22 normal adjacent tissue samples using an AKAP12 methylation-sensitive high-resolution melting assay. AKAP12 gene expression was also examined in 4 human prostate carcinoma cell lines, PC-3, DU145, LNCaP, and 22RV1, using quantitative reverse transcriptase-polymerase chain reaction and methylation-sensitive high-resolution melting analysis and after DNA methyltransferase inhibition with 5-aza-2′-deoxycytidine. Results Methylation (>1%) of the AKAP12 promoter region was present in 47 (60.2%) of the 78 PCa, 5 (22.7%) of the 22 benign prostatic hyperplasia, and 2 (9.1%) of the 22 adjacent normal tissue samples. AKAP12 methylation was significantly greater in the PCa than in the benign prostatic hyperplasia or adjacent tissue samples ( P AKAP12 methylation was significantly greater in the PCa samples with higher Gleason scores ( P = .03); however, no correlation was found with age, pT category, or serum prostate-specific antigen level. Reverse transcriptase-polymerase chain reaction demonstrated that PC-3 and DU-145 cells expressed AKAP12 RNA and LNCaP and 22RV1 did not. The AKAP12 locus was methylated in the LNCaP and 22RV1 cells. Treatment of LNCaP cells with 5-aza-2′-deoxycytidine markedly decreased the methylation levels and increased the expression of AKAP12 . Conclusions The results of the present study have demonstrated that AKAP12 promoter methylation is a frequent event in human PCa. AKAP12 methylation represents a potential molecular biomarker for predicting the malignancy of PCa.

  • rapid determination of AKAP12 promoter methylation levels in peripheral blood using methylation sensitive high resolution melting ms hrm analysis application in colorectal cancer
    Clinica Chimica Acta, 2010
    Co-Authors: Ming Guan, Bing Su, Ji Li, Min Li, Yuan Lu

    Abstract:

    Abstract Background Colorectal cancer is the third most common form of cancer and hypermethylation has been shown to increase the risk of developing this disease. DNA hypermethylation in the A kinase anchor protein 12 (AKAP12/Gravin) promoter region and the accompanied underexpression of it has been noted in a variety of human cancers. Methods We applied methylation-specific high resolution melting (MS-HRM) technology to detect quantitatively A kinase anchor protein 12 (AKAP12/Gravin) methylation in peripheral blood from 100 colorectal cancer patients and 50 healthy volunteers and in 3 colorectal cancer cell lines. Results In this study 48 of the 100 colorectal cancer samples (48%) were found to be methylated at the AKAP12 promoter region. AKAP12 methylation was significantly higher in the colorectal cancer samples with differentiation (p = 0.03). We also compared the results generated by MS-HRM with a traditional methylation-specific PCR (MSP) assay. We found that intra-assay variability ranged from 6.14 to 9.90% and inter-assay variability ranged from 14.5 to 17.2%. The AKAP12 MS-HRM assay was able to reproducibly detect 1% methylated DNA, whereas the MSP method was unable to detect less than 5% methylation. Conclusions We demonstrate the utility of quantitative AKAP12 MS-HRM analysis of promoter methylation in peripheral blood samples. AKAP12 MS-HRM quantitative methods with excellent detection capabilities have many promising applications in the research and diagnosis of colorectal cancer.