Table2_The Apoptotic Resistance of BRCA1-Deficient Ovarian Cancer Cells is Mediated by cAMP.XLSX

Breast cancer type 1 susceptibility protein (BRCA1) is essential for homologous recombination repair of DNA double-strand breaks. Loss of BRCA1 is lethal to embryos due to extreme genomic instability and the activation of p53-dependent apoptosis. However, the apoptosis is resisted in BRCA1-deficient cancer cells even though their p53 is proficient. In this study, by analysis of transcriptome data of ovarian cancer patients bearing BRCA1 defects in TCGA database, we found that cAMP signaling pathway was significantly activated. Experimentally, we found that BRCA1 deficiency caused an increased expression of ADRB1, a transmembrane receptor that can promote the generation of cAMP. The elevated cAMP not only inhibited DNA damage-induced apoptosis through abrogating p53 accumulation, but also suppressed the proliferation of cytotoxic T lymphocytes by enhancing the expression of immunosuppressive factors DKK1. Inhibition of ADRB1 effectively killed cancer cells by abolishing the apoptotic resistance. These findings uncover a novel mechanism of apoptotic resistance in BRCA1-deficient ovarian cancer cells and point to a potentially new strategy for treating BRCA1-mutated tumors.

乳腺癌1型易感蛋白（BRCA1）对于DNA双链断裂的同源重组修复至关重要。BRCA1缺失会因严重基因组不稳定及p53依赖性细胞凋亡的激活而导致胚胎致死。然而，即便p53功能正常，BRCA1缺陷的癌细胞仍会产生凋亡抵抗。本研究通过分析TCGA数据库中携带BRCA1缺陷的卵巢癌患者的转录组数据，发现环磷酸腺苷（cAMP）信号通路被显著激活。实验证实，BRCA1缺陷会上调β1肾上腺素能受体（ADRB1）的表达——该跨膜受体可促进cAMP的生成。升高的cAMP不仅通过阻断p53的积累抑制了DNA损伤诱导的细胞凋亡，还通过上调免疫抑制因子DKK1的表达抑制了细胞毒性T淋巴细胞的增殖。抑制ADRB1可有效消除癌细胞的凋亡抵抗，从而杀伤肿瘤细胞。本研究揭示了BRCA1缺陷卵巢癌细胞产生凋亡抵抗的全新机制，为BRCA1突变肿瘤的治疗提供了潜在新策略。