Inhibition of Ribonucleotide Reductase Induces Endoplasmic Reticulum Stress and Apoptosis, Leading to the Death of Docetaxel-resistant Prostate Cancer Cells

Abstract

Background: The development of chemotherapy resistance in prostate cancer (PCa) patients poses a significant obstacle to disease progression. Ribonucleotide reductase is a crucial enzyme for cell division and tumor growth. Triapine, an inhibitor of ribonucleotide reductase, has shown strong anti-tumor activity in various types of cancers. However, the effect of triapine on docetaxel-resistant (DR) human PCa cells has not been explored previously.

Aim: This study aimed to examine the potential anti-proliferative effects of triapine in PC3-DR (docetaxel-resistant) cells.

Methods: Cell viability was determined by the MTT test, and apoptosis and cell cycle progression were analyzed by image-based cytometer. mRNA and protein expression were assessed by RT-qPCR and western blot, respectively.

Results: Triapine administration significantly reduced PC3 and PC3-DR cells' survival, while the cytotoxic effect was higher in PC3-DR cells. Cell death resulting from inhibition of ribonucleotide reductase was mediated by endoplasmic reticulum stress, induction of apoptosis, and cell cycle arrest. The findings were supported by the upregulation of caspases, Bax, Bak, P21, P27, P53, TNF-α, FAS, and FASL, and downregulation of Bcl2, Bcl-XL, cyclin-dependent kinase 2 (CDK2), CDK4, cyclins, and heat shock proteins expression. According to the data, the reduction of ABC transporter proteins and NF-ĸB expression may play a role in triapine-mediated cytotoxicity in docetaxel-resistant cells.

Conclusion: Based on our findings, triapine emerges as a promising chemotherapeutic approach for combating docetaxel- resistant prostate cancer.

Keywords: Apoptosis; PC3; docetaxel; endoplasmic reticulum; prostate cancer; triapine.