mPTP sensitization and calcium channel remodeling: an adaptive response in carboplatin-resistant ovarian cancer cells

Abstract Acquired resistance to chemotherapy represents a major obstacle to the long-term efficacy of treatment in ovarian cancer. In this study, we investigated the impact of acquired resistance to Taxol® and carboplatin on mitochondrial permeability transition pore (mPTP) sensitivity and Ca²⁺ homeostasis in high-grade serous ovarian cancer (HGSOC) cells. Taxol®-resistant cells exhibited no detectable alterations in mPTP sensitivity or Ca²⁺ signaling. In contrast, carboplatin-resistant cells displayed increased mPTP sensitivity accompanied by a marked reduction in endoplasmic reticulum Ca²⁺ release, store-operated Ca²⁺ entry, constitutive Ca²⁺ entry, and mitochondrial Ca²⁺ uptake. These alterations were associated with reduced mRNA expression of Orai1, STIM1, KCNN2, KCNN3, and MCU. Consistent with these findings, low tumoral expression of ORAI1 was associated with disease progression and an unfavorable response to platinum-based treatment in patients with ovarian cancer. Short-term exposure to carboplatin was sufficient to sensitize the mPTP in non-cancerous HEK-293 cells, suggesting that this effect results from a direct action of the drug rather than from an adaptive phenotype acquired through prolonged drug selection. Pharmacological attenuation of carboplatin-induced mPTP sensitization using morusin was associated with increased basal mitochondrial Ca²⁺ and carboplatin-induced cytotoxicity. Taken together, our data support a two-steps model of cellular adaptation to carboplatin. The initial response involves increased mPTP sensitivity, which may promote the release of excess mitochondrial Ca²⁺. This is followed by a broader downregulation of Ca²⁺ entry pathways, thereby limiting the Ca²⁺ load reaching an intrinsically sensitized mPTP. Further studies are required to elucidate the molecular mechanisms linking these adaptive responses.