PMID- 25143389
OWN - NLM
STAT- MEDLINE
DCOM- 20141217
LR  - 20240102
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 40
DP  - 2014 Oct 3
TI  - Mechanism of metformin-dependent inhibition of mammalian target of rapamycin 
      (mTOR) and Ras activity in pancreatic cancer: role of specificity protein (Sp) 
      transcription factors.
PG  - 27692-701
LID - 10.1074/jbc.M114.592576 [doi]
AB  - 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 down-regulated specificity protein (Sp) transcription 
      factors (TFs) Sp1, 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.
CI  - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Nair, Vijayalekshmi
AU  - Nair V
AD  - From the Departments of Veterinary Physiology and Pharmacology and.
FAU - Sreevalsan, Sandeep
AU  - Sreevalsan S
AD  - From the Departments of Veterinary Physiology and Pharmacology and.
FAU - Basha, Riyaz
AU  - Basha R
AD  - the Cancer Research Institute, M.D. Anderson Cancer Center-Orlando, Orlando, 
      Florida 32806, the Baylor College of Medicine, Houston, Texas 77030.
FAU - Abdelrahim, Maen
AU  - Abdelrahim M
AD  - the Cancer Research Institute, M.D. Anderson Cancer Center-Orlando, Orlando, 
      Florida 32806, the Baylor College of Medicine, Houston, Texas 77030.
FAU - Abudayyeh, Ala
AU  - Abudayyeh A
AD  - the Department of Emergency Medicine, M.D. Anderson Cancer Center, Houston, Texas 
      77030, and.
FAU - Rodrigues Hoffman, Aline
AU  - Rodrigues Hoffman A
AD  - Veterinary Pathobiology, Texas A&M University, College Station, Texas 77843.
FAU - Safe, Stephen
AU  - Safe S
AD  - From the Departments of Veterinary Physiology and Pharmacology and the Institute 
      of Biosciences and Technology, Texas A&M Health Sciences Center, Houston, Texas 
      77030 ssafe@cvm.tamu.edu.
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - P30ES023512/ES/NIEHS NIH HHS/United States
GR  - R01CA136571/CA/NCI NIH HHS/United States
GR  - P30 ES023512/ES/NIEHS NIH HHS/United States
GR  - R01 CA136571/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140820
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Sp Transcription Factors)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Down-Regulation/drug effects
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Male
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Nude
MH  - Pancreatic Neoplasms/drug therapy/*genetics/metabolism
MH  - Signal Transduction
MH  - Sp Transcription Factors/*genetics/metabolism
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*genetics/metabolism
MH  - ras Proteins/antagonists & inhibitors/*genetics/metabolism
PMC - PMC4183806
OTO - NOTNLM
OT  - Epidermal Growth Factor Receptor (EGFR)
OT  - Gene Expression
OT  - IGFR Down-regulation
OT  - Insulin-like Growth Factor (IGF)
OT  - Metformin
OT  - Pancreatic Cancer
OT  - Ras Inhibition
OT  - Sp Transcription Factors
OT  - Specificity Protein 1 (Sp1)
OT  - mTOR Down-regulation
EDAT- 2014/08/22 06:00
MHDA- 2014/12/18 06:00
PMCR- 2015/10/03
CRDT- 2014/08/22 06:00
PHST- 2014/08/22 06:00 [entrez]
PHST- 2014/08/22 06:00 [pubmed]
PHST- 2014/12/18 06:00 [medline]
PHST- 2015/10/03 00:00 [pmc-release]
AID - S0021-9258(20)48405-4 [pii]
AID - M114.592576 [pii]
AID - 10.1074/jbc.M114.592576 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 Oct 3;289(40):27692-701. doi: 10.1074/jbc.M114.592576. Epub 
      2014 Aug 20.