Yang Yu1, Fu-Han Yang1, Wen-Tao Zhang1, Ya-Dong Guo1, Lin Ye2, Xu-Dong Yao3. 1. Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. 2. Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. ericyelin@163.com. 3. Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China. yaoxudong1967@163.com.
Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms. METHODS: The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. RESULTS: MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. CONCLUSIONS: These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.
BACKGROUND: Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms. METHODS: The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. RESULTS: MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. CONCLUSIONS: These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.
Authors: Nicholas Howard; Marco Clementino; Donghern Kim; Lei Wang; Angela Verma; Xianglin Shi; Zhuo Zhang; Robert S DiPaola Journal: Semin Cancer Biol Date: 2018-09-10 Impact factor: 15.707
Authors: Jeanine M L Roodhart; Laura G M Daenen; Edwin C A Stigter; Henk-Jan Prins; Johan Gerrits; Julia M Houthuijzen; Marije G Gerritsen; Henk S Schipper; Marieke J G Backer; Miranda van Amersfoort; Joost S P Vermaat; Petra Moerer; Kenji Ishihara; Eric Kalkhoven; Jos H Beijnen; Patrick W B Derksen; Rene H Medema; Anton C Martens; Arjan B Brenkman; Emile E Voest Journal: Cancer Cell Date: 2011-09-13 Impact factor: 31.743
Authors: Theodoros Karantanos; Christopher P Evans; Bertrand Tombal; Timothy C Thompson; Rodolfo Montironi; William B Isaacs Journal: Eur Urol Date: 2014-10-08 Impact factor: 20.096
Authors: Milad Ashrafizadeh; Mahshid Deldar Abad Paskeh; Sepideh Mirzaei; Mohammad Hossein Gholami; Ali Zarrabi; Farid Hashemi; Kiavash Hushmandi; Mehrdad Hashemi; Noushin Nabavi; Francesco Crea; Jun Ren; Daniel J Klionsky; Alan Prem Kumar; Yuzhuo Wang Journal: J Exp Clin Cancer Res Date: 2022-03-22