PTPN2 inhibits TG-induced ERS-initiated TNBC apoptosis through the mitochondrial pathway

Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer that portends a poor prognosis and limited treatment. PTPN2 is a member of the non-receptor protein tyrosine phosphatase family that regulates biological processes by dephosphorylating various signaling molecules. Endoplasmic reticulum stress (ERS) plays a dual regulatory role by promoting both survival and apoptosis. This study aims to elucidate the role of PTPN2 in mediating the pro-apoptotic effects of ERS induced by Thapsigargin (TG), and its influence on the fate of TNBC cells, utilizing both loss-of-function and gain-of-function methodologies. Our findings indicate that PTPN2 modulates TG-induced ERS via the IRE1-XBP1 and PERK/EIF2 alpha/ATF-4 signaling pathways. Furthermore, PTPN2 mitigates the TG-induced reduction in cell proliferation and the concomitant increase in apoptosis. Specifically, PTPN2 appears to inhibit several facets of TG-induced apoptosis, including: (1) Ca2+ elevation in mitochondria, (2) the production of reactive oxygen species (ROS), and (3) Bax/Bcl-2 augmentation which dictates mitochondria-mediated apoptosis. Additionally, we observed that the knockdown of PTPN2 enhances TG-induced autophagy; however, our results suggest that autophagy may serve a protective role against TG-induced apoptosis. Consequently, targeting PTPN2 in conjunction with ERS-inducing agents may represent a promising therapeutic strategy for the treatment of TNBC.