Caveolin-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in ovarian clear cell carcinoma

Among epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) remains markedly resistant to platinum-based chemotherapy, leading to poor clinical outcomes. In response to xenobiotic insults, caveolar platforms play crucial roles in modulating stress signaling responses in cancer cells. It has been hypothesized that caveolin-1 (Cav-1), a main component of the lipid raft, may regulate the response to platinum-based treatment in OCCC. The clinical transcriptomic evaluation demonstrated that high Cav-1 expression was positively associated with a favorable prognosis in patients with ovarian cancer. Cav-1 overexpression enhanced sensitivity to cisplatin (CDDP) treatment, whereas Cav-1 deficiency promoted chemoresistance in OCCC cells. Mechanistically, although Cav-1 counteracted angiotensin-converting enzyme 2 (ACE2) expression, ACE2 positively facilitated resistance to CDDP in OCCC cells. Furthermore, ACE2 restricted aryl hydrocarbon receptor expression and subsequent transcription of drug-metabolizing enzymes. Of note, ACE2 positively regulated the expression of the platinum-clearing enzyme CYP3A4. These findings suggest that the Cav-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in OCCC, predicting potential roles for the stress sentinel networks in oncogenic processes.