Senescence triggers intracellular acidification and lysosomal alkalinization via ATP6AP2 attenuation in breast cancer cells

Several chemotherapy drugs induce the senescence of cancer cells; however, the mechanism underlying intracellular pH dysregulation in senescent cells remains unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. We here report a new function of ATP6AP2 in senescent breast cancer cells induced by doxorubicin and abemaciclib treatment. ATP6AP2 expression was significantly downregulated in senescent cells, leading to aberrant pH levels that impaired lysosome function and caused immune response changes. The drugs caused cell cycle arrest and proliferation suppression through the upregulation of senescence-related genes. Additionally, senescent cells showed altered inflammatory and immune transcriptional profiles by reprogramming the senescence-associated secretory phenotype. These findings suggest that ATP6AP2-mediated pH regulation during therapy-induced senescence may be linked to immune changes in senescent cancer cells. These findings provide novel insights into understanding the cellular mechanisms underlying the response to anti-cancer drugs. ### Competing Interest Statement K.K.: grants from TERUMO, Astellas, Eli Lilly, Kyoto Breast Cancer Research Network; consulting fees from Becton Dickinson Japan; honoraria from Eisai, Chugai, and Takeda. M.T.: grants from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, JBCRG Associates, Eisai, Eli Lilly, Daiichi-Sankyo, AstraZeneca, Astellas, Shimadzu, Yakult, Nippon Kayaku, AFI Technology, Luxonus, Shionogi, and GL Science; honoraria from Chugai, Takeda, Pfizer, Kyowa-Kirin, Taiho, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science, Novartis, Konica Minolta, Shimadzu, Yakult, and Nippon Kayaku; advisory board of Kyowa-Kirin, Daiichi-Sankyo, Eli Lilly, Konica Minolta, BMS, Athenex Oncology, Bertis, Terumo, Kansai Medical Net; board of directors of JBCRG Associates, KBCRN, OOTR; Associate Editor of the British Journal of Cancer, Scientific Reports, Breast Cancer Research and Treatment, Cancer Science, Frontiers in Women's Cancer, Asian Journal of Surgery, Asian Journal of Breast Surgery; deputy editor of International Journal of Oncology.