title: Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo.
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 LKB1.
authors.affiliation: E423 Segal Cancer Centre of the Jewish General Hospital, Departments of Experimental Medicine and Oncology, McGill University, Montréal, Québec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Algire
authors.forename: L
authors.initials: L
authors.lastname: Amrein
authors.forename: M
authors.initials: M
authors.lastname: Bazile
authors.forename: S
authors.initials: S
authors.lastname: David
authors.forename: M
authors.initials: M
authors.lastname: Zakikhani
authors.forename: M
authors.initials: M
authors.lastname: Pollak
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung; D004032:Diet; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016147:Genes, Tumor Suppressor; D006946:Hyperinsulinism / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases