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V. Poulaki, M. Ooi, C. S. Mitsiades, J. W. Miller, N. Mitsiades; The Antidiabetic Biguanide Metformin Induces Growth Arrest in Retinoblastoma Cells in vitro . Invest. Ophthalmol. Vis. Sci. 2009;50(13):1699.
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Serine/threonine kinase 11 (STK11, also called LKB1) modulates energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germline and sporadic mutations of STK11 are associated with neoplasia, supporting the tumor suppressor role of the STK11/AMPK pathway. Restoration of wild-type STK11 causes senescence in cancer cell lines in an Rb-dependent manner. The antidiabetic agent metformin activates the STK11/AMPK pathway, and has been found to have direct, AMPK-dependent, anticancer activity in vitro against breast, prostate, colon, and ovarian carcinoma cell lines. Interestingly, epidemiologic studies have suggested that patients with type 2 diabetes mellitus who are treated with metformin have lower cancer incidence and lower cancer-related mortality than diabetics who receive sulfonylurea monotherapy or insulin.
We interrogated the Gene Expression Omnibus (GEO) database for expression of STK11 and AMPK mRNA in Rb clinical specimens (N=16). We also investigated the direct effects of the AMPK activator metformin in vitro in the Rb cell lines Y79 and WERI-Rb1 using the MTT assay, cell cycle analysis by flow cytometry and immunoblotting.
Our search in the GEO database revealed expression of AMPK and STK11 mRNA in human retinoblastomas. The AMPK activator metformin induced growth arrest in both Rb cell lines in vitro, at concentrations in the same order of magnitude reported to be active in solid tumor models. Metformin-induced growth arrest was associated with decrease in cyclin D1 levels and increase in phosphorylation of AMPK.
Our studies demonstrate a direct, growth-suppressive effect of the AMPK activator metformin in Rb cells in vitro. Metformin has been widely used as an antidiabetic agent since the 1950s and has an excellent safety profile. Activation of the STK11/AMPK pathway may serve as a treatment modality for human malignancies, including Rb.
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