Abstract
BackgroundMesenchymal 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.MethodsThe 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.ResultsMSCs 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.ConclusionsThese 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.
Highlights
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related mortality among men in the United States [1]
The results indicate that Mesenchymal stem cells (MSCs) could desensitize castration resistant prostate cancer (CRPC) cells to docetaxel chemotherapy and contribute to chemoresistance via inducing TGF-β1-mediated cell autophagy
To investigate whether MSCs could migrate into PCa sites, we performed frozen sections to detected green fluorescent protein (GFP) signals in tumors
Summary
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related mortality among men in the United States [1]. For locally advanced and metastatic PCa, androgen deprivation therapy (ADT) is currently considered as the most effective treatment, giving a 70% initial effective rate [3]. Almost all of them with initially castration-sensitive prostate cancer (CSPC) would eventually develop into castrationresistant prostate cancer (CRPC) after a period of ADT. Docetaxel-mediated antimitotic chemotherapy is typically used as the first-line standard treatment. Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). We aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms
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