Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer

Vijayalekshmi Nair, Sandeep Sreevalsan, Riyaz Basha, Maen Abdelrahlm, Ala Abudayyeh, Aline Rodrigues Hoffman, Stephen Safe

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The antidiabetic drug metformin exhibits both chemopreventive and chemotherapeutic activity for multiple cancers includ ing pancreatic cancer; however, the underlying mechanism of action of metformin is unclear. A recent study showed that metformin down-regulated specificity protein (Sp) transcription factors (TFs) Spl, Sp3, and Sp4 in pancreatic cancer cells and tumors, and this was accompanied by down-regulation of several pro-oncogenic Sp-regulated genes. Treatment with metformin or down-regulation of Sp TFs by RNAi also inhibits two major pro-oncogenic pathways in pancreatic cancer cells, namely mammalian target of rapamycin (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 down-regulation of Sp TFs and Sp-regulated IGF-1R and EGFR, which in turn results in inhibition of mTOR and Ras signaling, respectively.

Original languageEnglish
Pages (from-to)27692-27701
Number of pages10
JournalJournal of Biological Chemistry
Issue number40
StatePublished - 3 Oct 2014


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