Alisol B, a Novel Inhibitor of the Sarcoplasmic/Endoplasmic Reticulum Ca2+ ATPase Pump, Induces Autophagy, Endoplasmic Reticulum Stress, and Apoptosis

Abstract

Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G 1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. Mol Cancer Ther; 9(3); 718-30. ©2010 AACR.

Tgf-β1 induces autophagy and promotes apoptosis in renal tubular epithelial cells

“…Although autophagy was initially described as a cytoprotective mechanism under nutrient deprivation, several lines of evidence have indicated a role for autophagy in promoting cell death (7,15,22), similar to the results presented here in HRPTEpiCs. Some findings have shown that autophagy activation precedes TGF-β-induced apoptosis while blockade of Atg genes attenuates TGF-β-mediated apoptosis in hepatoma cells (17).…”

“…However, increasing evidence suggests that in response to excessive stress autophagy may be detrimental and can lead to cell death (5). Excessive autophagic activity may lead to cellular dysfunctions and induce death by destroying a large proportion of the cytosol and organelles, especially the mitochondria and the endoplasmic reticulum (ER) (6,7). The contribution of autophagy to cell death depends on the threshold of the stimuli.…”

Ca2+in quality control

“…29 Altered expression levels of BECN1 are associated with several human pathologies (summarized in Table 1 together with other pathologies associated with autophagy-related factors described in this review); reduced levels are characteristic of numerous cancers as well as Alzheimer disease, 33,34,45 whereas overexpression in vitro protects against infection by pathogens and myocardial infarction following ischemia/reperfusion. 46,47 Recent studies have shown other pharmacological agents that increase [Ca 2+ ] C also induce autophagy through the CAMKK2-PRKAA-MTOR pathway, 48,49 a cascade with established roles in multiple cellular processes including ribosome biogenesis and transcription in addition to cell motility and metabolism. 50 Furthermore, the formation of autophagic vesicles, induced by the Ca 2+ -dependent amyloid-β protein and observed in the brains of mice engineered to model Alzheimer disease, is also mediated through the same CAMKK2-PRKAA-MTOR pathway.…”

“…68 Similarly, compounds such as thapsigargin and alisol B that inhibit the action of ATP2A (ATPase, Ca 2+ transporting, cardiac muscle), prevent ER Ca 2+ uptake and thereby maintain elevated [Ca 2+ ] C , inducing autophagy. 25,48,52,54 Finally, Sakaki et al 69 established that PRKCQ (protein kinase C theta) is required for ER stress-induced autophagy. Increased [Ca 2+ ] C induces PRKCQ phosporylation and its localization to cytosolic MAP1LC3 puncta.…”

The Pivotal Neuroinflammatory, Therapeutic and Neuroprotective Role of Alpha-Mangostin

“…2017;7(4-5): [67][68][69][70][71][72][73][74][75][76][77][78][79] chondrial membrane depolarization and cytochrome C secretion in PC12 rat pheochromocytoma cells, which means that α-MG, stimulates programed cell death via the mitochondrial pathway. The type of the molecular processes associated with the secretion of cytochrome C which is a cardinal part of mitochondrial apoptotic pathway stimulation still remains a matter of debate [14].…”