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Metformin inhibits human T-cell leukemia virus type 1 transcription through activation of LKB1 and salt-inducible kinases

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Specific therapeutic and prophylactic agents are not available. Epidemiological studies have established a correlation between long-term use of the commonly prescribed anti-diabetic drug metformin and a decrease in the incidence of breast and other cancers. Whether metformin might also have anti-HTLV-1 and anti-ATL activity is unclear. In this study we demonstrate an inhibitory effect of metformin on HTLV-1 transcription mediated through the activation of LKB1 tumor suppressor and downstream salt-inducible kinases (SIKs). Treatment of HTLV-1- transformed ATL cells or cells transfected with HTLV-1 molecular clone pX1MT with metformin led to reduction in cell-free virion production and inhibition of cell proliferation. This effect was attributed to the activation of LKB1/SIK1 which compromised Tax expression and HTLV-1 transcription. LKB1 and SIKs function as host restriction factors that counteract Tax activation of HTLV-1 long terminal repeats. Expression of LKB1 and activated SIKs effectively blunted Tax activity in a phosphorylation-dependent manner in LKB1-null HeLa cells, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function in LKB1-proficient HEK293T cells. Activated LKB1 and SIKs associated with Tax. Enforced expression of LKB1 or SIK1 in pX1MT-transfected cells and HTLV-1-transformed ATL cells repressed proviral transcription, whereas depletion of LKB1 boosted Tax expression. Taken together, our findings revealed a potential therapeutic and prophylactic agent for ATL as well as a new negative regulatory function of LKB1 and SIKs in HTLV-1 transcription. (Supported by HKU7661/08M, HKU7674/12M, HKU1/CRF/11G and SKY-MRF-2011).

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Correspondence to Hei-Man V Tang.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Tang, HM.V., Gao, WW., Chan, CP. et al. Metformin inhibits human T-cell leukemia virus type 1 transcription through activation of LKB1 and salt-inducible kinases. Retrovirology 11 (Suppl 1), P112 (2014).

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