Reduced store operated calcium entry contributes to autophagy mediated escape of prostate cancer to oxaliplatin treatment

Oxaliplatin, a third-generation platinum-based chemotherapeutic drug, induces cell cycle arrest and apoptosis in prostate cancer treatment. However, both intrinsic and acquired resistance mechanisms limit its therapeutic efficacy. Notably, chemotherapeutic agents often induce autophagy-a cellular recycling process-that can contribute to drug resistance. Calcium (Ca²⁺) signalling plays a pivotal role in regulating cell fate. However, the involvement of Ca²⁺ and Ca²⁺ channels in oxaliplatin resistance within prostate cancer cells remains controversial and poorly understood. In this study, we demonstrate that oxaliplatin treatment enhances autophagy in prostate cancer cells. Concurrently, oxaliplatin modulates the expression of key proteins involved in store-operated calcium entry (SOCE): it upregulates Orai3 channels while downregulating Orai1 and Stim1. These alterations result in diminished SOCE activity, contributing to an apoptosis-resistant phenotype. Importantly, we found that targeting Orai3 expression and inhibiting autophagy sensitizes prostate cancer cells to oxaliplatin-induced apoptosis. Our findings suggest that combining Orai3 downregulation with autophagy inhibition may enhance the efficacy of oxaliplatin in treating prostate cancer. This combinatorial approach could hold potential for overcoming resistance and improving therapeutic outcomes.