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ABSTRACT Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding

the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated anti-neoplastic effects of metformin as compared with indirect effects attributable to reductions in

circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor

activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors

transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation _in

vitro_ showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent

energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin.

These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of

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Google Scholar  Download references ACKNOWLEDGEMENTS We thank Dr André Veillette for his advice and technical expertise, Dr Pnina Brodt for the MC38 cells, Drs Lawrence Panasci and Ernesto

Schiffrin for sharing laboratory resources, and Dr Nahum Sonenberg and Dr Russell Jones for reviewing the manuscript prior to submission. This work was supported by a grant from the Terry

Fox Research Institute. Ms Algire is supported through the Montréal Centre for Experimental Therapeutics in Cancer student fellowship and the Canadian Institute of Health Research Canada

Graduate Fellowship. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Departments of Experimental Medicine and Oncology, E423 Segal Cancer Centre of the Jewish General Hospital, McGill

University, Montréal, Québec, Canada C Algire & M Pollak * Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada L Amrein, M Bazile, S David & 

M Zakikhani Authors * C Algire View author publications You can also search for this author inPubMed Google Scholar * L Amrein View author publications You can also search for this author

inPubMed Google Scholar * M Bazile View author publications You can also search for this author inPubMed Google Scholar * S David View author publications You can also search for this author

inPubMed Google Scholar * M Zakikhani View author publications You can also search for this author inPubMed Google Scholar * M Pollak View author publications You can also search for this

author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to M Pollak. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION

Supplementary Information accompanies the paper on the Oncogene website SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURE 1A (PDF 90 KB) SUPPLEMENTARY FIGURE 1B (PDF 133 KB) SUPPLEMENTARY

FIGURE LEGEND (DOC 22 KB) SUPPLEMENTARY INFORMATION (DOC 21 KB) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Algire, C., Amrein, L., Bazile, M. _et

al._ Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin _in vivo_. _Oncogene_ 30, 1174–1182 (2011). https://doi.org/10.1038/onc.2010.483

Download citation * Received: 08 July 2010 * Revised: 01 September 2010 * Accepted: 13 September 2010 * Published: 22 November 2010 * Issue Date: 10 March 2011 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * metformin * insulin * cancer * LKB1