Affiliation:
1. Shandong University Cheeloo College of Medicine
2. Qilu Hospital of Shandong University
3. Universite de Strasbourg
Abstract
Abstract
Background
Castration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored.
Methods
Several public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as PCa patient outcomes. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and western blotting. Then both the biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo a series of experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms.
Results
PHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation conditions. PHB1 is an androgen receptor (AR) suppressive gene and androgen deprivation promotes the PHB1 expression and its nucleus-cytoplasm translocation. FL3, alone or combined with the antiandrogen drug Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive AR+ CRPC cells both in vitro and in vivo. By targeting the PHB1 protein, FL3 promoted its trafficking from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, but promoted apoptosis.
Conclusion
Our data indicated that PHB1 is abnormally upregulated in CRPC and involved in castration resistance and provided a novel rational therapeutic approach for CRPC.
Publisher
Research Square Platform LLC