Accumulating evidence indicates that indirubin exerts inhibitory effects on prostate cancer (PCa) progression. However, the role and underlying mechanisms of indirubin in sensitizing PCa to docetaxel remain unclear. CCK-8 assays were initially used to determine the effect of indirubin on enhancing docetaxel sensitivity in PCa cells. Following this, the expression levels of circ-Vav3 were quantified using quantitative real-time PCR (RT-qPCR) to evaluate its potential role in docetaxel resistance. Functional experiments, including flow cytometry-based apoptosis analysis and Transwell migration/invasion assays, were conducted to assess the impact of circ-Vav3 modulation and indirubin treatment on cell viability and behavior in response to docetaxel. Rescue experiments were subsequently performed to further confirm the regulatory effect of indirubin on circ-Vav3. Additionally, xenograft tumor models in nude mice were utilized to evaluate the therapeutic efficacy of indirubin in vivo. Mechanistic interactions between circ-Vav3, miR-204-5p, and MAPK1 were further investigated using RNA pulldown assays, luciferase reporter assays, and Western blot analyses. Indirubin enhanced the sensitivity of PCa cells to docetaxel by downregulating the expression of circ-Vav3, which was found to be significantly upregulated in docetaxel-resistant PCa cells. Silencing circ-Vav3 effectively reversed this resistance, as evidenced by increased apoptosis, reduced cell migration and invasion, and decreased autophagic activity. Notably, indirubin treatment suppressed circ-Vav3 expression and thereby restored docetaxel sensitivity both in vitro and in xenograft tumor models. Mechanistically, circ-Vav3 acted as a competing endogenous RNA (ceRNA) by sponging miR-204-5p, which led to the upregulation of the autophagy-related kinase MAPK1. Inhibition of MAPK1 effectively suppressed autophagy and re-sensitized docetaxel-resistant PCa cells, further confirming the critical regulatory role of the circ-Vav3/miR-204-5p/MAPK1 signaling axis in mediating chemoresistance. Our findings demonstrate that circ-Vav3 promotes docetaxel resistance in PCa by sponging miR-204-5p and subsequently activating MAPK1-mediated autophagy. Indirubin effectively restores chemosensitivity by targeting this regulatory pathway, offering a promising therapeutic strategy for overcoming chemoresistance in castration-resistant prostate cancer (CRPC).
Zheng et al. (Fri,) studied this question.