PMID- 23986086
OWN - NLM
STAT- MEDLINE
DCOM- 20140710
LR  - 20211203
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 4
IP  - 9
DP  - 2013 Sep
TI  - Dietary restriction-resistant human tumors harboring the PIK3CA-activating 
      mutation H1047R are sensitive to metformin.
PG  - 1484-95
AB  - Cancer cells expressing constitutively active phosphatidylinositol-3 kinase 
      (PI3K) are proliferative regardless of the absence of insulin, and they form 
      dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin 
      to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) 
      signaling cascade, activating mutations in the PIK3CA oncogene may determine 
      tumor response to DR-like pharmacological strategies targeting the insulin and 
      mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic 
      that exerts its anti-cancer activity through a dual mechanism involving 
      insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, 
      it remains unclear whether PIK3CA-activating mutations might preclude the 
      anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven 
      early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, 
      which harbors the gain-of-function H1047R hot-spot mutation in the catalytic 
      domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To 
      model PIK3CA-activating mutations in late stages of cancer, we took advantage of 
      the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated 
      tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com 
      xenotumors, although only modestly affected by treatment with oral metformin 
      (approximately 40% tumor growth inhibition), were highly sensitive to the 
      intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of 
      which increased in a time-dependent manner and reached >80% tumor growth 
      inhibition by the end of the treatment. Metformin treatment via the i.p. route 
      significantly reduced the proliferation factor mitotic activity index (MAI) and 
      decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas 
      SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors 
      in mice, ad libitum access to water containing metformin significantly reduced 
      the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. 
      Thus, metformin can no longer be considered as a bona fide DR mimetic, at least 
      in terms of anti-cancer activity, because tumors harboring the 
      insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain 
      sensitive to the anti-tumoral effects of the drug. Given the high prevalence of 
      PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation 
      status in the treatment selection process, these findings might have a 
      significant impact on the design of future trials evaluating the potential of 
      combining metformin with targeted therapy.
FAU - Cufi, Silvia
AU  - Cufi S
AD  - Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute 
      of Oncology, Girona, Catalonia, Spain.
FAU - Corominas-Faja, Bruna
AU  - Corominas-Faja B
FAU - Lopez-Bonet, Eugeni
AU  - Lopez-Bonet E
FAU - Bonavia, Rosa
AU  - Bonavia R
FAU - Pernas, Sonia
AU  - Pernas S
FAU - Lopez, Isabel Alvarez
AU  - Lopez IA
FAU - Dorca, Joan
AU  - Dorca J
FAU - Martinez, Susana
AU  - Martinez S
FAU - Lopez, Norberto Batista
AU  - Lopez NB
FAU - Fernandez, Severina Dominguez
AU  - Fernandez SD
FAU - Cuyas, Elisabet
AU  - Cuyas E
FAU - Visa, Joana
AU  - Visa J
FAU - Rodriguez-Gallego, Esther
AU  - Rodriguez-Gallego E
FAU - Quirantes-Pine, Rosa
AU  - Quirantes-Pine R
FAU - Segura-Carretero, Antonio
AU  - Segura-Carretero A
FAU - Joven, Jorge
AU  - Joven J
FAU - Martin-Castillo, Begona
AU  - Martin-Castillo B
FAU - Menendez, Javier A
AU  - Menendez JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Breast Neoplasms/*drug therapy/enzymology/*genetics/pathology
MH  - Cell Growth Processes/drug effects
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Diet
MH  - Female
MH  - Humans
MH  - Metformin/*pharmacology
MH  - Mice
MH  - Mice, Nude
MH  - Phosphatidylinositol 3-Kinases/*genetics/metabolism
MH  - Random Allocation
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC3824528
EDAT- 2013/08/30 06:00
MHDA- 2014/07/11 06:00
PMCR- 2013/09/01
CRDT- 2013/08/30 06:00
PHST- 2013/08/30 06:00 [entrez]
PHST- 2013/08/30 06:00 [pubmed]
PHST- 2014/07/11 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - 1234 [pii]
AID - 10.18632/oncotarget.1234 [doi]
PST - ppublish
SO  - Oncotarget. 2013 Sep;4(9):1484-95. doi: 10.18632/oncotarget.1234.