Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells
Wei Li, Kosuke Kawaguchi, Sunao Tanaka, Chenfeng He, Yurina Maeshima, Eiji Suzuki, Masakazu Toi
Abstract
Abstract 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.