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Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo
1E423 Segal Cancer Centre of the Jewish General Hospital, Departments of Experimental Medicine and Oncology, McGill University, Montréal, Québec, Canada.
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.
Insights
Metformin
Area of Science:
- Oncology
- Metabolic Disorders
- Molecular Biology
Background:
- Epidemiological studies suggest metformin reduces cancer burden in diabetics.
- The anti-neoplastic mechanisms of metformin, direct (AMPK-mediated) versus indirect (insulin reduction), are debated.
Purpose of the Study:
- To investigate the role of LKB1 expression and host insulin levels in metformin's anti-tumor effects.
- To elucidate the cellular mechanisms underlying metformin's action in different LKB1/AMPK contexts.
Main Methods:
- Utilized mouse models with diet-induced hyperinsulinemia and tumors with varying LKB1 expression (including LKB1 knockdown).
- Administered metformin and assessed tumor growth, insulin receptor activation, and cellular ATP levels.
- Conducted in vitro experiments to examine metformin sensitivity in cells with reduced LKB1.
Main Results:
- Metformin inhibited tumor growth and insulin receptor activation in hyperinsulinemic mice, irrespective of tumor LKB1 status.
- In non-hyperinsulinemic conditions, metformin only inhibited tumors with reduced LKB1, independent of host insulin or tumor AMPK activation.
- Cells with reduced LKB1 showed increased sensitivity to metformin-induced ATP depletion due to impaired energy conservation.
Conclusions:
- Metformin's efficacy in cancer treatment is dependent on both host insulin levels and tumor LKB1 functional status.
- Loss of LKB1 function can sensitize cancer cells to metformin by exacerbating ATP depletion.
- Clinical applications of metformin in oncology may be limited to specific patient subpopulations defined by metabolic and genetic factors.
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