Cargando…

Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Cifarelli, Vincenza, Lashinger, Laura M., Devlin, Kaylyn L., Dunlap, Sarah M., Huang, Jennifer, Kaaks, Rudolf, Pollak, Michael N., Hursting, Stephen D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407853/
https://www.ncbi.nlm.nih.gov/pubmed/25576058
http://dx.doi.org/10.2337/db14-1132
_version_ 1782367969022574592
author Cifarelli, Vincenza
Lashinger, Laura M.
Devlin, Kaylyn L.
Dunlap, Sarah M.
Huang, Jennifer
Kaaks, Rudolf
Pollak, Michael N.
Hursting, Stephen D.
author_facet Cifarelli, Vincenza
Lashinger, Laura M.
Devlin, Kaylyn L.
Dunlap, Sarah M.
Huang, Jennifer
Kaaks, Rudolf
Pollak, Michael N.
Hursting, Stephen D.
author_sort Cifarelli, Vincenza
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4407853
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher American Diabetes Association
record_format MEDLINE/PubMed
spelling pubmed-44078532016-05-01 Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms Cifarelli, Vincenza Lashinger, Laura M. Devlin, Kaylyn L. Dunlap, Sarah M. Huang, Jennifer Kaaks, Rudolf Pollak, Michael N. Hursting, Stephen D. Diabetes Obesity Studies 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. American Diabetes Association 2015-05 2015-01-09 /pmc/articles/PMC4407853/ /pubmed/25576058 http://dx.doi.org/10.2337/db14-1132 Text en © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Obesity Studies
Cifarelli, Vincenza
Lashinger, Laura M.
Devlin, Kaylyn L.
Dunlap, Sarah M.
Huang, Jennifer
Kaaks, Rudolf
Pollak, Michael N.
Hursting, Stephen D.
Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms
title Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms
title_full Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms
title_fullStr Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms
title_full_unstemmed Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms
title_short Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms
title_sort metformin and rapamycin reduce pancreatic cancer growth in obese prediabetic mice by distinct microrna-regulated mechanisms
topic Obesity Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407853/
https://www.ncbi.nlm.nih.gov/pubmed/25576058
http://dx.doi.org/10.2337/db14-1132
work_keys_str_mv AT cifarellivincenza metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT lashingerlauram metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT devlinkaylynl metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT dunlapsarahm metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT huangjennifer metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT kaaksrudolf metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT pollakmichaeln metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms
AT hurstingstephend metforminandrapamycinreducepancreaticcancergrowthinobeseprediabeticmicebydistinctmicrornaregulatedmechanisms