TY - JOUR
T1 - Mechanism of metformin-dependent inhibition of mammalian target of rapamycin (mTOR) and Ras activity in pancreatic cancer
AU - Nair, Vijayalekshmi
AU - Sreevalsan, Sandeep
AU - Basha, Riyaz
AU - Abdelrahlm, Maen
AU - Abudayyeh, Ala
AU - Hoffman, Aline Rodrigues
AU - Safe, Stephen
N1 - Publisher Copyright:
© 2014 by The American Society for Biochemistry and Molecular Biology Inc.
PY - 2014/10/3
Y1 - 2014/10/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84907495391&partnerID=8YFLogxK
U2 - 10.1074/jbc.M114.592576
DO - 10.1074/jbc.M114.592576
M3 - Article
C2 - 25143389
AN - SCOPUS:84907495391
SN - 0021-9258
VL - 289
SP - 27692
EP - 27701
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -