title: Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms.
abstract: Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin's PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle-regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.
authors.affiliation: Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Cifarelli
authors.affiliation: Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Lashinger
authors.affiliation: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX.
authors.forename: Kaylyn L
authors.initials: KL
authors.lastname: Devlin
authors.affiliation: Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dunlap
authors.affiliation: Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Huang
authors.affiliation: Division of Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.affiliation: Departments of Medicine and Oncology, McGill University, Montreal, Canada.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.affiliation: Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX Department of Nutrition, University of North Carolina, Chapel Hill, NC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC hursting@email.unc.edu.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
mesh_terms: D000818:Animals; D001835:Body Weight; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D003927:Diet, Diabetic; D002149:Energy Intake; D018149:Glucose Intolerance; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011236:Prediabetic State / Q000188:drug therapy*; D011897:Random Allocation; D020123:Sirolimus / Q000627:therapeutic use*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D007166:Immunosuppressive Agents; D035683:MicroRNAs; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D008687:Metformin; D020123:Sirolimus