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Targeting the Synergistic Crosstalk Between Insulin and G Protein-Coupled Receptor Signaling by Metformin Potently Inhibits Pancreatic Cancer Cell Proliferation in vitro and in vivo
K. Kisfalvi,1 J. Sinnett-Smith,1 G. Eibl,2 E. Rozengurt.1 1Department of Medicine, 2Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles.
Current therapies offer poor survival rates in pancreatic cancer patients. More
effective therapies will likely arise from targeting synergistic crosstalks in the
cancer cells that promote their unrestricted proliferation.
Results: We identified a crosstalk between insulin/IGF-1 and G proteincoupled
receptor (GPCR) agonist signaling pathways that synergize to
strikingly enhance cell proliferation and DNA synthesis in human pancreatic
cancer cells. This synergistic interaction depended on the function of mammalian
target of rapamycin (mTOR) Metformin, the most widely used drug
for type-2 diabetes, is thought to activate AMP kinase (AMPK), which
negatively regulates mTOR. We found that metformin abrogated the enhanced
DNA synthesis, anchorage-dependent and independent growth induced
by insulin and GPCR agonists in pancreatic cancer cells, including
PANC-1 and MIAPaCa-2. Metformin induced sustained AMPK activation
and AMPK inhibitor reversed the effects of metformin. Next we examined
how metformin affects pancreatic cancer growth in vivo using PANC-1 and
MIAPaCa-2 tumor xenografts in nude mice. Metformin, given daily intraperitoneally
(250 mg/kg) markedly decreased the rate of growth of both
PANC-1 and MIAPaCa-2 xenografts (p=0.007 in PANC-1, p=0.005 in
MIAPaCa-2). We then administered metformin orally, as currently available
for human patients, in drinking water (2.5mg/ml). Metformin again strongly
inhibited the growth of the tumor xenografts (p=0.014 in PANC-1, p=0.009
Conclusion: These results raise the possibility that metformin could be a
candidate in novel treatment strategies for human pancreatic cancer.
The exact mechanism responsible for the efficacy of metformin in treating this in vivo model of lung cancer has yet to be fully elucidated. What is clear, however, is the potential feasibility of this “new” drug as an important agent in the future management of lung cancer. Further, as the authors propose, this work has important implications for chemoprevention.1 There is strong rationale for proceeding with a chemoprevention trial that uses metformin in heavy smokers who are at high risk for developing lung cancer.
As we continue to search for fresh answers to old problems, we must realize that the wave of targeted molecular therapy for cancer is upon us. In order to provide individualized therapeutic plans for patients, ideally delivering the greatest benefit with the least burdensome side effects, we must understand the genetics of our patients' tumors and identify possible targets for intervention. Further, while billions of dollars and an enormous amount of effort will certainly continue to be directed toward the development and design of novel compounds, an important point has been made here: sometimes, all it takes is revisiting a “blast from the past.”