Atiprimod triggered apoptotic cell death via acting on PERK/eIF2α/ATF4/CHOP and STAT3/NF-ΚB axis in MDA-MB-231 and MDA-MB-468 breast cancer cells

Abstract

Purpose: The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth, and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes rst autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic e ciency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells.Results: Dose-and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 mM) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3 and NF-kB was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2a (Ser51) phosphorylation's. However, atiprimod suppressed IRE1a-mediated Atg-3, 5, 7, 12 protein expressions and no alteration were observed on Beclin-1, p62 expression levels. PERK/eIF2a/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression. Conclusion:Atiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2a/ATF4/CHOP axis and suppressing STAT3/NF-kB transcription factors nuclear migration in TBNC cells. HighlightsAtiprimod induced endoplasmic reticulum stress

Importin 7 enhances protective autophagy induced by nuclear translocation of homeobox A10 in oral squamous cell carcinoma

“…It is reported that Nox4 facilitates autophagy and osteoclastogenesis by the activation of the PERK/EIF2α/ATF4 signaling [29]. Atiprimod-induced ERS-mediated autophagy through regulating the PERK/EIF2α/ATF4/CHOP axis in breast cancer [30]. In this study, we found that IPO7 depletion markedly suppressed the EIF2AK3, ATF4, CHOP, and p-EIF2α levels.…”

Application of calcium overload-based ion interference therapy in tumor treatment: strategies, outcomes, and prospects

“…In parallel, the unfolded protein response (UPR) is also activated in reply to ER stress. Although the UPR might help reduce the load of unfolded proteins to maintain cell survival ( Marciniak et al, 2022 ), persistent UPR caused by long-term severe ER stress could induce apoptosis through protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)/CCAAT enhance-binding protein homologous protein (CHOP) pathway ( Hetz, 2012 ; Yu et al, 2021b ; Coker-Gurkan et al, 2021 ). As a transcription factor, CHOP promotes mitochondrial dependent apoptosis by upregulating the expression of pro-apoptotic proteins comprise BAX, BAK and BIM.…”

Photodynamic therapy with TBZPy regulates the PI3K/AKT and endoplasmic reticulum stress-related PERK/eIF2α pathways in HeLa cells

“…We then examined the effects of TBZPy-PDT on ER stress, which is a cellular response to various stimuli that disrupt ER homeostasis and cause accumulation of unfolded or misfolded proteins in the ER lumen (Grebenová et al, 2003). ER stress activates three major signaling pathways: PERK/eIF2α, IRE1/XBP1, and ATF6 (Coker-Gurkan et al, 2021;Walter and Ron, 2011). Among them, PERK/eIF2α is considered to be the main pathway involved in PDT-induced apoptosis (Chen et al, 2019).…”