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

Vincenza Cifarelli1, Laura M Lashinger2, Kaylyn L Devlin3

  • 1Department of Medicine, Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO.

Diabetes
|January 11, 2015
PubMed

Insights

Metformin and rapamycin inhibit pancreatic cancer growth in obese, prediabetic mice. They work through shared and distinct mechanisms, offering potential strategies to combat the diabetes-pancreatic cancer link.

Area of Science:

  • Oncology
  • Endocrinology
  • Molecular Biology

Background:

  • Metformin is linked to reduced pancreatic cancer (PC) risk and better prognosis in type 2 diabetes patients.
  • The mechanism of metformin's PC growth inhibition in prediabetic states remains unclear.

Purpose of the Study:

  • To investigate the mechanisms by which metformin and rapamycin inhibit PC growth in diet-induced obese (DIO) mice.
  • To compare their effects on tumor growth, glucose regulation, mTOR signaling, and microRNA (miR) expression.

Main Methods:

  • Utilized a Panc02 pancreatic tumor cell transplant model in DIO C57BL/6 mice.
  • Compared effects of metformin and rapamycin on PC growth, glucose, insulin, mTOR pathway, and miR expression.
  • Assessed tumor sphere formation and Notch inhibition in vitro.

Main Results:

  • Both metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR signaling in DIO/prediabetic mice.
  • Rapamycin decreased mTOR-regulated growth/survival signaling and increased let-7b and cell cycle-regulating miRs.
  • Metformin reduced glucose/insulin levels, miR-34a, Notch, Slug, and Snail, and inhibited Notch in tumor spheres.

Conclusions:

  • Metformin and rapamycin inhibit pancreatic tumor growth in obese, prediabetic mice via shared and distinct pathways.
  • Metformin uniquely impacts glucose/insulin regulation and specific miR targets.
  • Metformin and mTOR inhibitors show promise for intervention strategies targeting the diabetes-PC link.

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