Department of Breast Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto, 606-8507, Japan.
Kobe City Medical Center General Hospital, 2-1-1 Minatojimaminami-cho, Chuo-ku, Kobe, 650-0047, Japan.
Commun Biol. 2023 Nov 22;6(1):1147. doi: 10.1038/s42003-023-05433-6.
Several chemotherapeutic drugs induce senescence in cancer cells; however, the mechanisms underlying intracellular pH dysregulation in senescent cells remain unclear. Adenosine triphosphatase H transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. Herein, we report the regulatory role of ATP6AP2 in senescent breast cancer cells treated with doxorubicin (Doxo) and abemaciclib (Abe). A decline in ATP6AP2 triggers aberrant pH levels that impair lysosomal function and cause immune profile changes in senescent breast cancer cells. Doxo and Abe elicited a stable senescent phenotype and altered the expression of senescence-related genes. Additionally, senescent cells show altered inflammatory and immune transcriptional profiles due to reprogramming of the senescence-associated secretory phenotype. These findings elucidate ATP6AP2-mediated cellular pH regulation and suggest a potential link in immune profile alteration during therapy-induced senescence in breast cancer cells, providing insights into the mechanisms involved in the senescence response to anticancer therapy.
几种化疗药物可诱导癌细胞衰老；然而，衰老细胞中细胞内 pH 失调的机制尚不清楚。三磷酸腺苷酶 H 转运辅助蛋白 2（ATP6AP2）在维持细胞区室的 pH 稳态中发挥关键作用。在此，我们报告了 ATP6AP2 在阿霉素（Doxo）和阿贝西利（Abe）处理的衰老乳腺癌细胞中的调节作用。ATP6AP2 的下降引发异常的 pH 水平，损害溶酶体功能，并导致衰老乳腺癌细胞的免疫特征发生变化。Doxo 和 Abe 引起稳定的衰老表型，并改变与衰老相关的基因表达。此外，衰老细胞由于衰老相关分泌表型的重编程而显示出改变的炎症和免疫转录特征。这些发现阐明了 ATP6AP2 介导的细胞 pH 调节，并提示在乳腺癌细胞治疗诱导的衰老过程中免疫特征改变的潜在联系，为涉及抗癌治疗的衰老反应的机制提供了深入了解。
