title: Resveratrol prevents rapamycin-induced upregulation of autophagy and selectively induces apoptosis in TSC2-deficient cells.
abstract: The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is hyperactivated in a variety of cancers and disorders, including lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC), which are characterized by mutations in tumor suppressors TSC1 or TSC2. The concern with the use of mTORC1 inhibitors, such as rapamycin or its analogs (rapalogs), is that they cause upregulation of autophagy and suppress the negative feedback loop to Akt, which promotes cell survival, causing the therapy to be only partially effective, and relapse occurs upon cessation of treatment. In this study, we investigate the use of rapamycin in combination with resveratrol, a naturally occurring polyphenol, in TSC2-deficient cells. We tested whether such combination would prevent rapamycin-induced upregulation of autophagy and shift the cell fate toward apoptosis. We found that this combination treatment blocked rapamycin-induced upregulation of autophagy and restored inhibition of Akt. Interestingly, the combination of rapamycin and resveratrol selectively promoted apoptosis of TSC2-deficient cells. Thus, the addition of resveratrol to rapamycin treatment may be a promising option for selective and targeted therapy for diseases with TSC loss and mTORC1 hyperactivation.
authors.affiliation: Department of Biology; Stern College for Women of Yeshiva University; New York, NY USA.
authors.forename: Anya
authors.initials: A
authors.lastname: Alayev
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biology; Stern College for Women of Yeshiva University; New York, NY USA.
authors.forename: Rose B
authors.initials: RB
authors.lastname: Snyder
authors.affiliation: Department of Biology; Stern College for Women of Yeshiva University; New York, NY USA.
authors.forename: Sara Malka
authors.initials: SM
authors.lastname: Berger
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School; Boston, MA USA.
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
authors.affiliation: Department of Biology; Stern College for Women of Yeshiva University; New York, NY USA; Department of Molecular Pharmacology; Stern College for Women of Yeshiva University; New York, NY USA; Albert Einstein Cancer Center; Albert Einstein College of Medicine; Bronx, NY USA.
authors.forename: Marina K
authors.initials: MK
authors.lastname: Holz
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002478:Cells, Cultured; D004357:Drug Synergism; D006801:Humans; D018192:Lymphangioleiomyomatosis; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D046912:Multiprotein Complexes; D013267:Stilbenes; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000077185:Resveratrol; D020123:Sirolimus
keywords: LAM; TSC; apoptosis; autophagy; mTOR; rapamycin; resveratrol