Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells.
Wei LiKosuke KawaguchiSunao TanakaChenfeng HeYurina MaeshimaEiji SuzukiMasakazu ToiPublished in: Communications biology (2023)
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.
Keyphrases
- breast cancer cells
- transcription factor
- dna damage
- endothelial cells
- stress induced
- induced apoptosis
- cell cycle arrest
- high glucose
- oxidative stress
- poor prognosis
- gene expression
- cell death
- reactive oxygen species
- signaling pathway
- endoplasmic reticulum stress
- mesenchymal stem cells
- binding protein
- cell therapy
- long non coding rna
- protein protein
- protein kinase
- heat shock