title: Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation.
abstract: We recently demonstrated that resveratrol induces caspase-dependent apoptosis in multiple cancer cell types. Whether apoptosis is also regulated by other cell death mechanisms such as autophagy is not clearly defined. Here we show that inhibition of autophagy enhanced resveratrol-induced caspase activation and apoptosis. Resveratrol inhibited colony formation and cell proliferation in multiple cancer cell types. Resveratrol treatment induced accumulation of LC3-II, which is a key marker for autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased resveratrol-mediated caspase activation and cell death in breast and colon cancer cells. Inhibition of autophagy by silencing key autophagy regulators such as ATG5 and Beclin-1 enhanced resveratrol-induced caspase activation. Mechanistic analysis revealed that Beclin-1 did not interact with proapoptotic proteins Bax and Bak; however, Beclin-1 was found to interact with p53 in the cytosol and mitochondria upon resveratrol treatment. Importantly, resveratrol depleted ATPase 8 gene, and thus, reduced mitochondrial DNA (mtDNA) content, suggesting that resveratrol induces damage to mtDNA causing accumulation of dysfunctional mitochondria triggering autophagy induction. Together, our findings indicate that induction of autophagy during resveratrol-induced apoptosis is an adaptive response.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Prabhu
authors.forename: Pragya
authors.initials: P
authors.lastname: Srivastava
authors.forename: Neelu
authors.initials: N
authors.lastname: Yadav
authors.forename: Michael
authors.initials: M
authors.lastname: Amadori
authors.forename: Andrea
authors.initials: A
authors.lastname: Schneider
authors.forename: Athul
authors.initials: A
authors.lastname: Seshadri
authors.forename: Jason
authors.initials: J
authors.lastname: Pitarresi
authors.forename: Rachael
authors.initials: R
authors.lastname: Scott
authors.forename: Honghao
authors.initials: H
authors.lastname: Zhang
authors.forename: Shahriar
authors.initials: S
authors.lastname: Koochekpour
authors.forename: Raghu
authors.initials: R
authors.lastname: Gogada
authors.forename: Dhyan
authors.initials: D
authors.lastname: Chandra
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D017209:Apoptosis; D001343:Autophagy; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004272:DNA, Mitochondrial; D013267:Stilbenes; D020169:Caspases; D000077185:Resveratrol
keywords: Apoptosis; Autophagy; Mitochondria; Mitochondrial DNA; Resveratrol