Physapruin A Exerts Endoplasmic Reticulum Stress to Trigger Breast Cancer Cell Apoptosis via Oxidative Stress

Abstract

Physalis plants are commonly used traditional medicinal herbs, and most of their extracts containing withanolides show anticancer effects. Physapruin A (PHA), a withanolide isolated from P. peruviana, shows antiproliferative effects on breast cancer cells involving oxidative stress, apoptosis, and autophagy. However, the other oxidative stress-associated response, such as endoplasmic reticulum (ER) stress, and its participation in regulating apoptosis in PHA-treated breast cancer cells remain unclear. This study aims to explore the function of oxidative stress and ER stress in modulating the proliferation and apoptosis of breast cancer cells treated with PHA. PHA induced a more significant ER expansion and aggresome formation of breast cancer cells (MCF7 and MDA-MB-231). The mRNA and protein levels of ER stress-responsive genes (IRE1α and BIP) were upregulated by PHA in breast cancer cells. The co-treatment of PHA with the ER stress-inducer (thapsigargin, TG), i.e., TG/PHA, demonstrated synergistic antiproliferation, reactive oxygen species generation, subG1 accumulation, and apoptosis (annexin V and caspases 3/8 activation) as examined by ATP assay, flow cytometry, and western blotting. These ER stress responses, their associated antiproliferation, and apoptosis changes were partly alleviated by the N-acetylcysteine, an oxidative stress inhibitor. Taken together, PHA exhibits ER stress-inducing function to promote antiproliferation and apoptosis of breast cancer cells involving oxidative stress.

Research progress on the beneficial effects of exercise on endocrine system-related diseases in women by regulating ER stress pathways

“…ER stress inducer, tunicamycin, is a nucleotide antibiotic produced by actinomycetes. The mRNA and protein levels of ER stressresponsive genes (IRE1α and BIP) were upregulated in breast cancer cells [41]. The results showed that ER stress induced apoptosis in MDA-MB-231 by upregulating the expression of PERK, eIF2α, ATF4, CHOP, and caspase 4 that calpain could be a potential target for BC therapy [42].…”

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“…11,12 In a study, it was shown that Physapruin A, which has an antiproliferative effect, exhibited ER stress-inducing function to promote the proliferation and apoptosis of breast cancer cells containing oxidative stress. 13 ER, stress results in the activation of the UPR, which plays a primary role in stress adaptation, inducing apoptosis in affected cells when stress is not resolved. 14,15 The UPR is controlled by protein kinase RNA-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6).…”