Nifuroxazide induces the apoptosis of human non‑small cell lung cancer cells through the endoplasmic reticulum stress PERK signaling pathway

Abstract

The aim of the present study was to investigate the molecular mechanism of nifuroxazide (NFZ) in the induction of apoptosis of NCI-H1299 human non-small cell lung cancer (NSCLC) cells through the reactive oxygen species (ROS)/Ca 2+ /protein kinase R-like ER kinase (PERK)-activating transcription factor 4 (ATF4)-DNA damage inducible transcript 3 (CHOP) signaling pathway. Morphological changes of cells were observed by microscopy, and the apoptosis and intracellular ROS levels of cells were observed by inverted fluorescence microscopy. Cell viability after the addition of the PERK inhibitor, GSK2606414, were detected by Cell Counting Kit-8 assay. Annexin V-FITC was used to detect cell apoptosis, Brite 670 was used to detect intracellular ROS and Fura Red AM was used to detect Ca 2+ content. Western blotting was used to detect PERK, phosphorylated (P)-PERK, ATF4, CHOP, P-Janus kinase 2 and P-signal transducer and activator of transcription 3 expression levels. Compared with the dimethyl sulfoxide control group, NFZ inhibited the survival activity in the H1299 NSCLC cell line, in a time-and dose-dependent manner. However, GSK2606414 inhibited the NFZ-induced apoptosis of H1299 cells. GSK2606414 also inhibited the increase in ROS and Ca 2+ in H1299 cells induced by NFZ. Western blotting results demonstrated that NFZ significantly increased the expression levels of P-PERK, ATF4 and CHOP, whereas GSK2606414 significantly reduced the NFZ-induced increase in these protein expression levels. In conclusion, NFZ may induce the apoptosis of H1299 NSCLC cells through the ROS/Ca 2+ /PERK-ATF4-CHOP signaling pathway.

Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway

“…In addition, we used the PERK inhibitor GSK2606414 to investigate the role of SERCA dysfunction-induced PERK/elF2α/CHOP signaling activation in mediating heat stress-induced apoptosis in HT22 cells. Studies have demonstrated that GSK2606414 effectively inhibits the PERK-eIF2α axis, thereby attenuating neuronal apoptosis induced by endoplasmic reticulum stress, improving neuropathological damage, memory, and motor function impairments, and preventing neurodegeneration in Parkinson’s disease model [ 39 ]. In this study, we initially observed no significant change in SERCA expression when compared to the HS group, suggesting that PERK may function downstream of SERCA and that heat exposure might first induce alterations in SERCA levels, subsequently leading to endoplasmic reticulum stress (ERS).…”

NCI 159456 PERK Inhibitor as a Targeted Therapy for Lung Cancer: An In Vitro Study

“…However, this study was stopped because of a lack of efficacy based on strict progression-free survival (PFS) criteria at a futility interim analysis [41]. Nifuroxazide was demonstrated to induce the apoptosis of H1299 NSCLC cells via the ROS/Ca 2+ /PERK-ATF4-DNA damage-inducible transcript 3 (CHOP) signaling pathway [42], and butein (3,4,2 ′ ,4 ′ -tetrahydroxychalcone) was also reported to induced apoptosis and G2/M cell cycle arrest via the PERK/eIF2α/CHOP pathway in A549 and PC-9 NSCLC cell lines [43].…”

Heat stress induces calcium dyshomeostasis to subsequent cognitive impairment through ERS-mediated apoptosis via SERCA/PERK/eIF2α pathway

“…In addition, we used the PERK inhibitor GSK2606414 to investigate the role of SERCA dysfunction-induced PERK/elF2α/CHOP signaling activation in mediating heat stress-induced apoptosis in HT22 cells. Studies have demonstrated that GSK2606414 effectively inhibits the PERK-eIFα axis, thereby attenuating neuronal apoptosis induced by endoplasmic reticulum stress, improving neuropathological damage, memory, and motor function impairments, and preventing neurodegeneration in a Parkinson's disease model (Li et al, 2023). In this study, we initially observed no significant change in SERCA expression when compared to the HS group, suggesting that PERK may function downstream of SERCA and that heat exposure might first induce alterations in SERCA levels, subsequently leading to endoplasmic reticulum stress (ERS).…”