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

Cell Biology and Toxicology - Tập 39 - Trang 1181-1201 - 2022
Arulkumar Nagappan1, Ki-Hyung Kim1,2,3, Yuseok Moon1,3,4
1Laboratory of Mucosal Exposome and Biomodulation, Department of Integrative Biomedical Sciences, Pusan National University, Yangsan, Korea
2Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Busan, Korea
3Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
4Graduate Program of Genomic Data Sciences, Pusan National University, Yangsan, Korea

Tóm tắt

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.

Tài liệu tham khảo

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