Dual Regulation of Epithelial-Mesenchymal Transition and Mitochondrial Quality Control by Olivomycin A in Renal Cancer Cells

Here, we show that the aureolic acid-class antibiotic, olivomycin A, exerts potent anticancer activity in renal cell carcinoma (RCC) by disrupting both cell survival and metastatic programs. In A-498 (wild-type p53) and 786-O (loss-of-function in p53 and PTEN) cells, olivomycin A markedly inhibited migratory capacity and reversed epithelial–mesenchymal transition (EMT), as shown by downregulation of nuclear Snail and the mesenchymal marker N-cadherin, restoration of the epithelial markers, E-cadherin and ZO-1. In parallel, olivomycin A induced apoptosis through distinct p53-dependent mechanisms: In A-498 cells, apoptosis was primarily mediated via the intrinsic pathway, characterized by upregulation of Puma, and Bak, activated caspase-9. In 786-O cells, in contrast, both intrinsic and extrinsic cascades were engaged, as evidenced by caspase-8 activation, Bid truncation, and concurrent mitochondrial involvement. Notably, in p53-mutant 786-O cells, treatment with olivomycin A elicited severe genotoxic stress accompanied by robust DNA damage signaling, excessive reactive oxygen species (ROS) accumulation, and lysosomal activation, culminating in extensive mitochondrial clearance through mitophagy. Such changes were weaker in p53-wild-type A-498 cells, suggesting that the altered p53 context sensitizes RCC cells to olivomycin A-mediated mitochondrial quality control mechanisms. Collectively, our findings delineate a multifaceted mechanism whereby olivomycin A coordinates EMT suppression, apoptotic induction, and mitophagy. Thus, olivomycin A has potential as a therapeutic candidate that can target both survival and metastatic pathways in heterogeneous genetic backgrounds.