The Experts below are selected from a list of 11634 Experts worldwide ranked by ideXlab platform
Tomohiko Asano - One of the best experts on this subject based on the ideXlab platform.
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Ritonavir and ixazomib kill bladder cancer cells by causing Ubiquitinated Protein accumulation
Cancer science, 2017Co-Authors: Akinori Sato, Takako Asano, Kazuki Okubo, Makoto Isono, Tomohiko AsanoAbstract:There is no curative treatment for advanced bladder cancer. Causing Ubiquitinated Protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock Protein 90 and increase the amount of unfolded Proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded Proteins and thereby causing Ubiquitinated Proteins to accumulate. The combination of ritonavir and ixazomib induced drastic apoptosis and inhibited the growth of bladder cancer cells synergistically. The combination decreased the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the sub-G1 fraction significantly. Mechanistically, the combination caused Ubiquitinated Protein accumulation and endoplasmic reticulum stress. The combination-induced apoptosis was markedly attenuated by the Protein synthesis inhibitor cycloheximide, suggesting that the accumulation of Ubiquitinated Proteins played an important role in the combination's antineoplastic activity. Furthermore, the combination induced histone acetylation cooperatively and the decreased expression of histone deacetylases was thought to be one mechanism of this histone acetylation. The present study provides a theoretical basis for future development of novel Ubiquitinated-Protein-accumulation-based therapies effective against bladder cancer.
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bortezomib and belinostat inhibit renal cancer growth synergistically by causing Ubiquitinated Protein accumulation and endoplasmic reticulum stress
Biomedical Reports, 2015Co-Authors: Takako Asano, Akinori Sato, Kazuki Okubo, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing Ubiquitinated Protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded Proteins in cells by inhibiting heat-shock Protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing Ubiquitinated Protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). The combination also suppressed colony formation significantly (P<0.05). As co-treatment with the pan-caspase inhibitor Z-VAD-FMK changed the number of Annexin V-positive cells, this combination-induced apoptosis was considered caspase dependent. Mechanistically, the combination synergistically caused Ubiquitinated Proteins to accumulate and induced ER stress, as evidenced by the increased expression of glucose-regulated Protein 78 and HSP70. To the best of our knowledge, this is the first study demonstrating the beneficial combined effect of bortezomib and belinostat in renal cancer cells. The study provides a basis for clinical studies with the combination in patients with advanced renal cancer.
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Bortezomib and belinostat inhibit renal cancer growth synergistically by causing Ubiquitinated Protein accumulation and endoplasmic reticulum stress
Biomedical reports, 2015Co-Authors: Takako Asano, Akinori Sato, Kazuki Okubo, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing Ubiquitinated Protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded Proteins in cells by inhibiting heat-shock Protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing Ubiquitinated Protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes
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panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and Ubiquitinated Protein accumulation in renal cancer cells
BMC Urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor panobinostat hinders the refolding of unfolded Proteins by increasing the acetylation of heat shock Protein 90. We investigated whether combining panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded Proteins, thereby causing Ubiquitinated Proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and Ubiquitinated Protein accumulation were assessed. The combination of panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murine subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantly (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-tubulin was consistent with the suppression of HDAC6 activity by panobinostat, and the combination was shown to induce ER stress and Ubiquitinated Protein accumulation synergistically. Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and Ubiquitinated Protein accumulation. The current study provides a basis for testing the combination in patients with advanced renal cancer.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and Ubiquitinated Protein accumulation in renal cancer cells.
BMC urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor panobinostat hinders the refolding of unfolded Proteins by increasing the acetylation of heat shock Protein 90. We investigated whether combining panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded Proteins, thereby causing Ubiquitinated Proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and Ubiquitinated Protein accumulation were assessed. The combination of panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes
Hongyu Zhang - One of the best experts on this subject based on the ideXlab platform.
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nerve growth factor induced akt mtor activation protects the ischemic heart via restoring autophagic flux and attenuating Ubiquitinated Protein accumulation
Oncotarget, 2017Co-Authors: Zhouguang Wang, Yan Huang, Hongyu Zhang, Maoping Chu, Xiaofan Wang, Xueqiang Guang, Yingzheng Zhao, Chunxiang Zhang, Jian XiaoAbstract:// Zhou-Guang Wang 1, 2, 3, * , Hao Li 1, * , Yan Huang 2, * , Rui Li 2 , Xiao-Fan Wang 2 , Li-Xia Yu 2 , Xue-Qiang Guang 1 , Lei Li 1 , Hong-Yu Zhang 2 , Ying-Zheng Zhao 2 , Chunxiang Zhang 1 , Xiao-Kun Li 2, 3 , Rong-Zhou Wu 1 , Mao-Ping Chu 1 , Jian Xiao 1, 2 1 Institute of Cardiovascular Development and Translational Medicine, Children’s Heart Center, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325027, China 2 Molecular Pharmacology Research Center, School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou 325035, China 3 Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, 130012, China * These authors have contributed equally to this work Correspondence to: Jian Xiao, email: xfxj2000@126.com Mao-Ping Chu, email: chmping@126.com Rong-Zhou Wu, email: wrz71@hotmail.com Keywords: NGF, myocardial ischemia/reperfusion, autophagy, PI3K/Akt/mTOR, ubiquitin Received: April 14, 2016 Accepted: December 06, 2016 Published: December 27, 2016 ABSTRACT The dysregulation of autophagy is related to a variety of cardiovascular diseases, such as myocardial ischemia/reperfusion (I/R). Nerve growth factor (NGF) has been shown to have therapeutic potential in ischaemic heart injury. In this study, we demonstrate that NGF administration can accelerate autophagic flux and attenuate Protein ubiquitination in myocardial I/R heart. Our results showed that NGF could restored heart function and decreased the apoptosis of cardiomyocytes which induced by myocardial I/R injury. The protective effect of NGF is associated with the inhibition of autophagy related Proteins. On another hand, NGF enhances the clearance of Ubiquitinated Protein and increases the survival of myocardial cell in vivo and in vitro . Additionally, NGF could activate the PI3K/AKT and mTOR signaling pathways. These results suggested that the cardioprotective effect of NGF is related to the restoration of autophagic flux and attenuation of Protein ubiquitination via the activation of PI3K/AKT and mTOR pathway.
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bFGF regulates autophagy and Ubiquitinated Protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway
Scientific reports, 2015Co-Authors: Zhouguang Wang, Yue Wang, Yan Huang, Lei Zheng, Wen-ke Feng, Yanlong Liu, Hongyu ZhangAbstract:Autophagy is involved in the development and/or progression of many diseases, including myocardial ischemia/reperfusion (I/R). In this study, we hypothesized a protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and Ubiquitinated Protein accumulation is involved in the myocardial I/R model. Our results showed that bFGF improved heart function recovery and increased the survival of cardiomyocytes in myocardial I/R model. The protective effect of bFGF is related to the inhibition of LC3II levels. Additionally, bFGF enhances the clearance of Ub by p62 and increases the survival of H9C2 cells. Moreover, silencing of p62 partially blocks the clearance of Ub and abolishes the anti-apoptosis effect of bFGF. An shRNA against the autophagic machinery Atg7 increased the survival of H9C2 cells co-treated with bFGF and rapamycin. bFGF activates the downstream signaling of the PI3K/Akt/mTOR pathway. These results indicate that the role of bFGF in myocardial I/R recovery is related to the inhibition of excessive autophagy and increased Ubiquitinated Protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new direction for bFGF drug development for heart disease and identifies Protein signaling pathways involved in bFGF action.
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bfgf regulates autophagy and Ubiquitinated Protein accumulation induced by myocardial ischemia reperfusion via the activation of the pi3k akt mtor pathway
Scientific Reports, 2015Co-Authors: Zhouguang Wang, Yue Wang, Yan Huang, Lei Zheng, Wen-ke Feng, Yanlong Liu, Hongyu Zhang, Maoping Chu, Jian XiaoAbstract:Autophagy is involved in the development and/or progression of many diseases, including myocardial ischemia/reperfusion (I/R). In this study, we hypothesized a protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and Ubiquitinated Protein accumulation is involved in the myocardial I/R model. Our results showed that bFGF improved heart function recovery and increased the survival of cardiomyocytes in myocardial I/R model. The protective effect of bFGF is related to the inhibition of LC3II levels. Additionally, bFGF enhances the clearance of Ub by p62 and increases the survival of H9C2 cells. Moreover, silencing of p62 partially blocks the clearance of Ub and abolishes the anti-apoptosis effect of bFGF. An shRNA against the autophagic machinery Atg7 increased the survival of H9C2 cells co-treated with bFGF and rapamycin. bFGF activates the downstream signaling of the PI3K/Akt/mTOR pathway. These results indicate that the role of bFGF in myocardial I/R recovery is related to the inhibition of excessive autophagy and increased Ubiquitinated Protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new direction for bFGF drug development for heart disease and identifies Protein signaling pathways involved in bFGF action.
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Regulation of Autophagy and Ubiquitinated Protein Accumulation by bFGF Promotes Functional Recovery and Neural Protection in a Rat Model of Spinal Cord Injury
Molecular neurobiology, 2013Co-Authors: Hongyu Zhang, Zhouguang Wang, Xiao-xia Kong, Jie Yang, Bei-bei Lin, Shi-ping Zhu, Li Lin, Chao-shi GanAbstract:The role of autophagy in the recovery of spinal cord injury remains controversial; in particular, the mechanism of autophagy regulated degradation of Ubiquitinated Proteins has not been discussed to date. In this study, we investigated the protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and Ubiquitinated Protein accumulation is involved in the rat model of trauma. bFGF administration improved recovery and increased the survival of neurons in spinal cord lesions in the rat model. The protective effect of bFGF is related to the inhibition of autophagic Protein LC3II levels; bFGF treatment also enhances clearance of Ubiquitinated Proteins by p62, which also increases the survival of neuronal PC-12 cells. The activation of the downstream signals of the PI3K/Akt/mTOR pathway by bFGF treatment was detected both in vivo and in vitro. Combination therapy including the autophagy activator rapamycin partially abolished the protective effect of bFGF. The present study illustrates that the role of bFGF in SCI recovery is related to the inhibition of excessive autophagy and enhancement of Ubiquitinated Protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new trend for bFGF drug development for central nervous system injuries and sheds light on Protein signaling involved in bFGF action.
Zhouguang Wang - One of the best experts on this subject based on the ideXlab platform.
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nerve growth factor induced akt mtor activation protects the ischemic heart via restoring autophagic flux and attenuating Ubiquitinated Protein accumulation
Oncotarget, 2017Co-Authors: Zhouguang Wang, Yan Huang, Hongyu Zhang, Maoping Chu, Xiaofan Wang, Xueqiang Guang, Yingzheng Zhao, Chunxiang Zhang, Jian XiaoAbstract:// Zhou-Guang Wang 1, 2, 3, * , Hao Li 1, * , Yan Huang 2, * , Rui Li 2 , Xiao-Fan Wang 2 , Li-Xia Yu 2 , Xue-Qiang Guang 1 , Lei Li 1 , Hong-Yu Zhang 2 , Ying-Zheng Zhao 2 , Chunxiang Zhang 1 , Xiao-Kun Li 2, 3 , Rong-Zhou Wu 1 , Mao-Ping Chu 1 , Jian Xiao 1, 2 1 Institute of Cardiovascular Development and Translational Medicine, Children’s Heart Center, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou 325027, China 2 Molecular Pharmacology Research Center, School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou 325035, China 3 Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Jilin University, Changchun, 130012, China * These authors have contributed equally to this work Correspondence to: Jian Xiao, email: xfxj2000@126.com Mao-Ping Chu, email: chmping@126.com Rong-Zhou Wu, email: wrz71@hotmail.com Keywords: NGF, myocardial ischemia/reperfusion, autophagy, PI3K/Akt/mTOR, ubiquitin Received: April 14, 2016 Accepted: December 06, 2016 Published: December 27, 2016 ABSTRACT The dysregulation of autophagy is related to a variety of cardiovascular diseases, such as myocardial ischemia/reperfusion (I/R). Nerve growth factor (NGF) has been shown to have therapeutic potential in ischaemic heart injury. In this study, we demonstrate that NGF administration can accelerate autophagic flux and attenuate Protein ubiquitination in myocardial I/R heart. Our results showed that NGF could restored heart function and decreased the apoptosis of cardiomyocytes which induced by myocardial I/R injury. The protective effect of NGF is associated with the inhibition of autophagy related Proteins. On another hand, NGF enhances the clearance of Ubiquitinated Protein and increases the survival of myocardial cell in vivo and in vitro . Additionally, NGF could activate the PI3K/AKT and mTOR signaling pathways. These results suggested that the cardioprotective effect of NGF is related to the restoration of autophagic flux and attenuation of Protein ubiquitination via the activation of PI3K/AKT and mTOR pathway.
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bFGF regulates autophagy and Ubiquitinated Protein accumulation induced by myocardial ischemia/reperfusion via the activation of the PI3K/Akt/mTOR pathway
Scientific reports, 2015Co-Authors: Zhouguang Wang, Yue Wang, Yan Huang, Lei Zheng, Wen-ke Feng, Yanlong Liu, Hongyu ZhangAbstract:Autophagy is involved in the development and/or progression of many diseases, including myocardial ischemia/reperfusion (I/R). In this study, we hypothesized a protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and Ubiquitinated Protein accumulation is involved in the myocardial I/R model. Our results showed that bFGF improved heart function recovery and increased the survival of cardiomyocytes in myocardial I/R model. The protective effect of bFGF is related to the inhibition of LC3II levels. Additionally, bFGF enhances the clearance of Ub by p62 and increases the survival of H9C2 cells. Moreover, silencing of p62 partially blocks the clearance of Ub and abolishes the anti-apoptosis effect of bFGF. An shRNA against the autophagic machinery Atg7 increased the survival of H9C2 cells co-treated with bFGF and rapamycin. bFGF activates the downstream signaling of the PI3K/Akt/mTOR pathway. These results indicate that the role of bFGF in myocardial I/R recovery is related to the inhibition of excessive autophagy and increased Ubiquitinated Protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new direction for bFGF drug development for heart disease and identifies Protein signaling pathways involved in bFGF action.
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bfgf regulates autophagy and Ubiquitinated Protein accumulation induced by myocardial ischemia reperfusion via the activation of the pi3k akt mtor pathway
Scientific Reports, 2015Co-Authors: Zhouguang Wang, Yue Wang, Yan Huang, Lei Zheng, Wen-ke Feng, Yanlong Liu, Hongyu Zhang, Maoping Chu, Jian XiaoAbstract:Autophagy is involved in the development and/or progression of many diseases, including myocardial ischemia/reperfusion (I/R). In this study, we hypothesized a protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and Ubiquitinated Protein accumulation is involved in the myocardial I/R model. Our results showed that bFGF improved heart function recovery and increased the survival of cardiomyocytes in myocardial I/R model. The protective effect of bFGF is related to the inhibition of LC3II levels. Additionally, bFGF enhances the clearance of Ub by p62 and increases the survival of H9C2 cells. Moreover, silencing of p62 partially blocks the clearance of Ub and abolishes the anti-apoptosis effect of bFGF. An shRNA against the autophagic machinery Atg7 increased the survival of H9C2 cells co-treated with bFGF and rapamycin. bFGF activates the downstream signaling of the PI3K/Akt/mTOR pathway. These results indicate that the role of bFGF in myocardial I/R recovery is related to the inhibition of excessive autophagy and increased Ubiquitinated Protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new direction for bFGF drug development for heart disease and identifies Protein signaling pathways involved in bFGF action.
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Regulation of Autophagy and Ubiquitinated Protein Accumulation by bFGF Promotes Functional Recovery and Neural Protection in a Rat Model of Spinal Cord Injury
Molecular neurobiology, 2013Co-Authors: Hongyu Zhang, Zhouguang Wang, Xiao-xia Kong, Jie Yang, Bei-bei Lin, Shi-ping Zhu, Li Lin, Chao-shi GanAbstract:The role of autophagy in the recovery of spinal cord injury remains controversial; in particular, the mechanism of autophagy regulated degradation of Ubiquitinated Proteins has not been discussed to date. In this study, we investigated the protective role of basic fibroblast growth factor (bFGF) both in vivo and in vitro and demonstrated that excessive autophagy and Ubiquitinated Protein accumulation is involved in the rat model of trauma. bFGF administration improved recovery and increased the survival of neurons in spinal cord lesions in the rat model. The protective effect of bFGF is related to the inhibition of autophagic Protein LC3II levels; bFGF treatment also enhances clearance of Ubiquitinated Proteins by p62, which also increases the survival of neuronal PC-12 cells. The activation of the downstream signals of the PI3K/Akt/mTOR pathway by bFGF treatment was detected both in vivo and in vitro. Combination therapy including the autophagy activator rapamycin partially abolished the protective effect of bFGF. The present study illustrates that the role of bFGF in SCI recovery is related to the inhibition of excessive autophagy and enhancement of Ubiquitinated Protein clearance via the activation of PI3K/Akt/mTOR signaling. Overall, our study suggests a new trend for bFGF drug development for central nervous system injuries and sheds light on Protein signaling involved in bFGF action.
Maria E. Figueiredo-pereira - One of the best experts on this subject based on the ideXlab platform.
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Dynamics of the Degradation of Ubiquitinated Proteins by Proteasomes and Autophagy ASSOCIATION WITH SEQUESTOSOME 1/p62
Journal of Biological Chemistry, 2011Co-Authors: Natura Myeku, Maria E. Figueiredo-pereiraAbstract:Abstract Proteotoxicity resulting from accumulation of damaged/unwanted Proteins contributes prominently to cellular aging and neurodegeneration. Proteasomal removal of these Proteins upon covalent polyubiquitination is highly regulated. Recent reports proposed a role for autophagy in clearance of diffuse Ubiquitinated Proteins delivered by p62/SQSTM1. Here, we compared the turnover dynamics of endogenous Ubiquitinated Proteins by proteasomes and autophagy by assessing the effect of their inhibitors. Autophagy inhibitors bafilomycin A1, ammonium chloride, and 3-methyladenine failed to increase Ubiquitinated Protein levels. The proteasome inhibitor epoxomicin raised Ubiquitinated Protein levels at least 3-fold higher than the lysosomotropic agent chloroquine. These trends were observed in SK-N-SH cells under serum or serum-free conditions and in WT or Atg5−/− mouse embryonic fibroblasts (MEFs). Notably, chloroquine considerably inhibited proteasomes in SK-N-SH cells and MEFs. In these cells, elevation of p62/SQSTM1 was greater upon proteasome inhibition than with all autophagy inhibitors tested and was reduced in Atg5−/− MEFs. With epoxomicin, soluble p62/SQSTM1 associated with proteasomes and p62/SQSTM1 aggregates contained inactive proteasomes, Ubiquitinated Proteins, and autophagosomes. Prolonged autophagy inhibition (96 h) failed to elevate Ubiquitinated Proteins in rat cortical neurons, although epoxomicin did. Moreover, prolonged autophagy inhibition in cortical neurons markedly increased p62/SQSTM1, supporting its degradation mainly by autophagy and not by proteasomes. In conclusion, we clearly demonstrate that pharmacologic or genetic inhibition of autophagy fails to elevate Ubiquitinated Proteins unless the proteasome is affected. We also provide strong evidence that p62/SQSTM1 associates with proteasomes and that autophagy degrades p62/SQSTM1. Overall, the function of p62/SQSTM1 in the proteasomal pathway and autophagy requires further elucidation.
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Cytoskeleton/endoplasmic reticulum collapse induced by prostaglandin J2 parallels centrosomal deposition of Ubiquitinated Protein aggregates
The Journal of biological chemistry, 2006Co-Authors: Kenyon D Ogburn, Maria E. Figueiredo-pereiraAbstract:Abstract Many neurodegenerative disorders, such as Parkinson disease, exhibit inclusion bodies containing Ubiquitinated Proteins. The mechanisms implicated in this aberrant Protein deposition remain elusive. In these disorders signs of inflammation are also apparent in the affected central nervous system areas. We show that prostaglandin J2 (PGJ2), an endogenous product of inflammation, disrupts the cytoskeleton in neuronal cells. Furthermore, PGJ2 perturbed microtubule polymerization in vitro and decreased the number of free sulfhydryl groups on tubulin cysteines. A direct effect of PGJ2 on actin was not apparent, although actin filaments were altered in cells treated with PGJ2. This cyclopentenone prostaglandin triggered endoplasmic reticulum (ER) collapse and the redistribution of ER Proteins, such as calnexin and catechol-O-methyltransferase, into a large centrosomal aggregate containing Ubiquitinated Proteins and α-synuclein. The PGJ2-dependent cytoskeletal rearrangement paralleled the development of the large centrosomal aggregate. Both of these events were replicated by treating cells with colchicine, which disrupts the microtubule/ER network, but not with brefeldin A, which impairs ER/Golgi transport. PGJ2 also perturbed 26 S proteasome assembly and activity, which preceded the accumulation of Ubiquitinated Proteins as detergent/salt-insoluble aggregates. Our data support a mechanism by which, upon PGJ2 treatment, cytoskeleton/ER collapse coincides with the relocation of ER Proteins, other potentially neighboring Proteins, and Ubiquitinated Proteins into centrosomal aggregates. Development of these large perinuclear aggregates is associated with disruption of the microtubule/ER network. This aberrant Protein deposition, triggered by a product of inflammation, may be common to other compounds that disrupt microtubules and induce Protein aggregation, such as MPP+ and rotenone, found to be associated with neurodegeneration.
Akinori Sato - One of the best experts on this subject based on the ideXlab platform.
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Ritonavir and ixazomib kill bladder cancer cells by causing Ubiquitinated Protein accumulation
Cancer science, 2017Co-Authors: Akinori Sato, Takako Asano, Kazuki Okubo, Makoto Isono, Tomohiko AsanoAbstract:There is no curative treatment for advanced bladder cancer. Causing Ubiquitinated Protein accumulation and endoplasmic reticulum stress is a novel approach to cancer treatment. The HIV protease inhibitor ritonavir has been reported to suppress heat shock Protein 90 and increase the amount of unfolded Proteins in the cell. If the proteasome functions normally, however, they are rapidly degraded. We postulated that the novel proteasome inhibitor ixazomib combined with ritonavir would kill bladder cancer cells effectively by inhibiting degradation of these unfolded Proteins and thereby causing Ubiquitinated Proteins to accumulate. The combination of ritonavir and ixazomib induced drastic apoptosis and inhibited the growth of bladder cancer cells synergistically. The combination decreased the expression of cyclin D1 and cyclin-dependent kinase 4, and increased the sub-G1 fraction significantly. Mechanistically, the combination caused Ubiquitinated Protein accumulation and endoplasmic reticulum stress. The combination-induced apoptosis was markedly attenuated by the Protein synthesis inhibitor cycloheximide, suggesting that the accumulation of Ubiquitinated Proteins played an important role in the combination's antineoplastic activity. Furthermore, the combination induced histone acetylation cooperatively and the decreased expression of histone deacetylases was thought to be one mechanism of this histone acetylation. The present study provides a theoretical basis for future development of novel Ubiquitinated-Protein-accumulation-based therapies effective against bladder cancer.
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bortezomib and belinostat inhibit renal cancer growth synergistically by causing Ubiquitinated Protein accumulation and endoplasmic reticulum stress
Biomedical Reports, 2015Co-Authors: Takako Asano, Akinori Sato, Kazuki Okubo, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing Ubiquitinated Protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded Proteins in cells by inhibiting heat-shock Protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing Ubiquitinated Protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). The combination also suppressed colony formation significantly (P<0.05). As co-treatment with the pan-caspase inhibitor Z-VAD-FMK changed the number of Annexin V-positive cells, this combination-induced apoptosis was considered caspase dependent. Mechanistically, the combination synergistically caused Ubiquitinated Proteins to accumulate and induced ER stress, as evidenced by the increased expression of glucose-regulated Protein 78 and HSP70. To the best of our knowledge, this is the first study demonstrating the beneficial combined effect of bortezomib and belinostat in renal cancer cells. The study provides a basis for clinical studies with the combination in patients with advanced renal cancer.
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Bortezomib and belinostat inhibit renal cancer growth synergistically by causing Ubiquitinated Protein accumulation and endoplasmic reticulum stress
Biomedical reports, 2015Co-Authors: Takako Asano, Akinori Sato, Kazuki Okubo, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing Ubiquitinated Protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded Proteins in cells by inhibiting heat-shock Protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing Ubiquitinated Protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes
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panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and Ubiquitinated Protein accumulation in renal cancer cells
BMC Urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor panobinostat hinders the refolding of unfolded Proteins by increasing the acetylation of heat shock Protein 90. We investigated whether combining panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded Proteins, thereby causing Ubiquitinated Proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and Ubiquitinated Protein accumulation were assessed. The combination of panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). It also suppressed colony formation significantly (p <0.05). In a murine subcutaneous tumor model, a 10-day treatment was well tolerated and inhibited tumor growth significantly (p <0.05). Enhanced acetylation of the HDAC6 substrate alpha-tubulin was consistent with the suppression of HDAC6 activity by panobinostat, and the combination was shown to induce ER stress and Ubiquitinated Protein accumulation synergistically. Panobinostat inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and Ubiquitinated Protein accumulation. The current study provides a basis for testing the combination in patients with advanced renal cancer.
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Panobinostat synergizes with bortezomib to induce endoplasmic reticulum stress and Ubiquitinated Protein accumulation in renal cancer cells.
BMC urology, 2014Co-Authors: Akinori Sato, Takako Asano, Makoto Isono, Keiichi Ito, Tomohiko AsanoAbstract:Inducing endoplasmic reticulum (ER) stress is a novel strategy used to treat malignancies. Inhibition of histone deacetylase (HDAC) 6 by the HDAC inhibitor panobinostat hinders the refolding of unfolded Proteins by increasing the acetylation of heat shock Protein 90. We investigated whether combining panobinostat with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded Proteins, thereby causing Ubiquitinated Proteins to accumulate and induce ER stress. Caki-1, ACHN, and 769-P cells were treated with panobinostat and/or bortezomib. Cell viability, clonogenicity, and induction of apoptosis were evaluated. The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model. The combination-induced ER stress and Ubiquitinated Protein accumulation were assessed. The combination of panobinostat and bortezomib induced apoptosis and inhibited renal cancer growth synergistically (combination indexes
