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.

Graphical abstract

中文翻译：

---

Caveolin-1-ACE2 轴调节卵巢透明细胞癌中异生素代谢相关的化疗耐药性

在上皮性卵巢癌中，卵巢透明细胞癌（OCCC）仍然对铂类化疗具有明显耐药性，导致临床结果不佳。为了应对外源性损伤，小凹平台在调节癌细胞的应激信号反应中发挥着至关重要的作用。据推测，脂筏的主要成分 Caveolin-1 (Cav-1) 可能调节 OCCC 对铂类治疗的反应。临床转录组学评估表明，Cav-1 的高表达与卵巢癌患者的良好预后呈正相关。Cav-1 过表达增强了对顺铂 (CDDP) 治疗的敏感性，而 Cav-1 缺乏则促进了 OCCC 细胞的化疗耐药性。从机制上讲，虽然 Cav-1 抵消了血管紧张素转换酶 2 (ACE2) 的表达，但 ACE2 确实促进了 OCCC 细胞对 CDDP 的抵抗。此外，ACE2 限制芳基碳氢化合物受体的表达和随后药物代谢酶的转录。值得注意的是，ACE2 正向调节铂清除酶 CYP3A4 的表达。这些发现表明，Cav-1-ACE2 轴调节 OCCC 中与外源代谢相关的化学耐药性，预测应激前哨网络在致癌过程中的潜在作用。

图形概要