An Yanhe, Lan Jinxin, Tang Jiaping, Luo Na
Department of Anatomy and Histology, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
Life Science Research Center, The First Affiliated Hospital of Xinxiang Medical University, Weihui, 453100, Henan, China.
Sci Rep. 2025 Jun 6;15(1):19896. doi: 10.1038/s41598-025-04312-w.
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/EIF2α/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) Ca 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.
三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性的亚型，预后较差且治疗手段有限。PTPN2是非受体蛋白酪氨酸磷酸酶家族的成员，通过使各种信号分子去磷酸化来调节生物过程。内质网应激（ERS）通过促进细胞存活和凋亡发挥双重调节作用。本研究旨在利用功能丧失和功能获得方法，阐明PTPN2在介导毒胡萝卜素（TG）诱导的ERS促凋亡作用及其对TNBC细胞命运的影响中的作用。我们的研究结果表明，PTPN2通过IRE1-XBP1和PERK/EIF2α/ATF-4信号通路调节TG诱导的ERS。此外，PTPN2减轻了TG诱导的细胞增殖减少和伴随的凋亡增加。具体而言，PTPN2似乎抑制了TG诱导凋亡的几个方面，包括：（1）线粒体中Ca升高，（2）活性氧（ROS）的产生，以及（3）决定线粒体介导凋亡的Bax/Bcl-2增加。此外，我们观察到PTPN2的敲低增强了TG诱导的自噬；然而，我们的结果表明自噬可能对TG诱导的凋亡起到保护作用。因此，联合靶向PTPN2和ERS诱导剂可能是治疗TNBC的一种有前景的治疗策略。
