Effects+of+metformin+on+mRNA+expression+of+mTOR

A study conducted by researchers from the University of Oklahoma Health Sciences Center in Oklahoma City, OK and the Chemopreventative Agent Development Research Group from Bethesda, MD looked at the effects of metformin on PanIN and their progression to PDAC in p48 Cre/+ .LSL-Kras G12D/+ mice. Within this study they analyzed, among other things, the expression of mTOR mRNA in mice fed diets of varying dosages of metformin and metformin-free diets (Ref. 1). Because mTOR is vital to cell proliferation and the reduction of apoptosis, it becomes a key player in the growth of tumors. In the case of pancreatic cancer, we see the over-activation of the PI3K/Akt/mTOR pathway which boosts a cancer cell's ability to growth and proliferate within the pancreatic tissues (Ref. 1).

In this study, mTOR expression and its related signalling molecules were analyzed using quantitative, real-time PCR. Frozen samples of pancreatic tissue from the mice were also analyzed for fold change increases in mRNA expression for a variety of proteins and transcription factors including mTOR, Rheb, cyclin D1, among others (Ref. 1). Rheb is a GTP-binding protein involved in growth and cell cycle progression while Cyclin D1 is a CDK 4/6 regulatory protein. If mutations, amplifications, or over-expression of cyclin D1 occurs tumorigenesis can occur because of the proteins direct link with cell cycle regulation. The following image shows results from this experiment, analyzing the mRNA expression of mTOR in p48 Cre/+ .LSL-Kras G12D/+ mice fed metformin-supplemented diets of varying amounts (ppm) in comparision with mice fed an AIN-76A diet alone (the control) (Ref. 1). The mice fed diets with metformin showed nearly two fold decreases in mTOR, Rheb, and Cyclin D1 expression (Figure 1.A,B,E).


 * Figure 1.** Effect of metformin on expression of mRNA for mTOR, Rheb, Cyclin D1, and others as determined by real-time quantitative PCR.

This drug certainly seems to be effective at decreasing the expression of certain proteins and transcription factors contributing to the continued growth of pancreatic cancer cells, however, as the primary researchers of this study pointed out, "It is important to elucidate whether this antidiabetic drug can exert direct effects on //in vivo// transgenic animal models of PC that recapitulate the stepwise progression of precursor lesions to carcinoma as seen in humans" (Ref. 1). We have seen test results that suggest a mechanism that should work in humans, but cancer in human pancreatic tissue is much more complex than in these simple mice models. It would be interesting to see the results of a similar test in humans, or at least in human cells grown in culture. These type of experiments would be telling if the mechanism of metformin affecting the expression of mTOR mRNA, and other related proteins, holds true in human cells.