Mechanism of Metformin-dependent Inhibition of mTOR and Ras Activity in Pancreatic Cancer: Role of Sp Transcription Factors [Gene Regulation]

August 20th, 2014 by Nair, V., Sreevalsan, S., Basha, R., Abdelrahim, M., Abudayyeh, A., Rodrigues Hoffman, A., Safe, S. H.

The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers including pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin downregulated specificity protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4 in pancreatic cancer cells and tumors and this was accompanied by downregulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or downregulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mTOR signaling and epidermal growth factor (EGFR)-dependent activation of Ras. Metformin and Sp knockdown by RNAi decreased expression of the insulin-like growth factor-1 receptor (IGF-1R) resulting in inhibition of mTOR signaling. Ras activity was also decreased by metformin and Sp knockdown of EGFR, another Sp-regulated gene. Thus, the antineoplastic activities of metformin in pancreatic cancer are due, in part, to downregulation of Sp TFs and Sp-regulated IGF-1R and EGFR which in turn result in inhibition of mTOR and Ras signaling, respectively.
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