The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment

作者：Bisheng Cheng, Lingfeng Li, Yongxin Wu, Tianlong Luo, Chen Tang, Qiong Wang, Qianghua Zhou, Jilin Wu, Yiming Lai, Dingjun Zhu, Tao Du, Hai Huang · 发表于：Cell & Bioscience · 年份：2023 · DOI：10.1186/s13578-023-01157-6 · 被引用次数：30 · 研究领域：Metal-Catalyzed Oxygenation Mechanisms、Heme Oxygenase-1 and Carbon Monoxide、Acute Myeloid Leukemia Research

BACKGROUND: Prostate cancer is a leading cause of cancer-related deaths among men worldwide. Docetaxel chemotherapy has proven effective in improving overall survival in patients with castration-resistant prostate cancer (CRPC), but drug resistance remains a considerable clinical challenge. METHODS: We explored the role of Ribonucleotide reductase subunit M2 (RRM2), a gene associated with senescence, in the sensitivity of prostate cancer to docetaxel. We evaluated the RRM2 expression, docetaxel resistance, and ANXA1 expression in prostate cancer cell lines and tumour xenografts models. In addition, We assessed the impact of RRM2 knockdown, ANXA1 over-expression, and PI3K/AKT pathway inhibition on the sensitivity of prostate cancer cells to docetaxel. Furthermore, we assessed the sensitivity of prostate cancer cells to the combination treatment of COH29 and docetaxel. RESULTS: Our results demonstrated a positive association between RRM2 expression and docetaxel resistance in prostate cancer cell lines and tumor xenograft models. Knockdown of RRM2 increased the sensitivity of prostate cancer cells to docetaxel, suggesting its role in mediating resistance. Furthermore, we observed that RRM2 stabilizes the expression of ANXA1, which in turn activates the PI3K/AKT pathway and contributes to docetaxel resistance. Importantly, we found that the combination treatment of COH29 and docetaxel resulted in a synergistic effect, further augmenting the sensitivity of prostate cancer cells t...