Docetaxel radiosensitizes castration-resistant prostate cancer by downregulating CAV-1

Abstract

Purpose: Docetaxel (DXL), a noted radiosensitizer, is one of the few chemotherapy drugs approved for castration-resistant prostate cancer (CRPC), though only a fraction of CRPCs respond to it. CAV-1, a critical regulator of radioresistance, has been known to modulate DXL and radiation effects. Combining DXL with radiotherapy may create a synergistic anticancer effect through CAV-1 and improve CRPC patients’ response to therapy. Here, we investigate the effectiveness and molecular characteristics of DXL and radiation combination therapy in vitro. Materials and methods: We used live/dead assays to determine the IC50 of DXL for PC3, DU-145, and TRAMP-C1 cells. Colony formation assay was used to determine the radioresponse of the same cells treated with radiation with/without IC50 DXL (4, 8, and 12 Gy). We performed gene expression analysis on public transcriptomic data collected from human-derived prostate cancer cell lines (C4-2, PC3, DU-145, and LNCaP) treated with DXL for 8, 16, and 72 hours. Cell cycle arrest and protein expression were assessed using flow cytometry and western blot, respectively. Results: Compared to radiation alone, combination therapy with DXL significantly increased CRPC death in PC3 (1.48-fold, p < .0001), DU-145 (1.64-fold, p < .05), and TRAMP-C1 (1.13-fold, p < .05) at 4 Gy of radiation. Gene expression of CRPC treated with DXL revealed downregulated genes related to cell cycle regulation and upregulated genes related to immune activation and oxidative stress. Confirming the results, G2/M cell cycle arrest was significantly increased after treatment with DXL and radiation. CAV-1 protein expression was decreased after DXL treatment in a dose-dependent manner; furthermore, CAV-1 copy number was strongly associated with poor response to therapy in CRPC patients. Conclusions: Our results suggest that DXL sensitizes CRPC cells to radiation by downregulating CAV-1. DXL + radiation combination therapy may be effective at treating CRPC, especially subtypes associated with high CAV-1 expression, and should be studied further.