Metformin inhibits human T-cell leukemia virus type 1 transcription through activation of LKB1 and...
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POSTER PRESENTATION Open Access Metformin inhibits human T-cell leukemia virus type 1 transcription through activation of LKB1 and salt-inducible kinases Hei-Man V Tang 1* , Wei-Wei Gao 1 , Ching-Ping Chan 1 , Yeung-Tung Siu 1 , Chi-Ming Wong 1 , Kin-Hang Kok 1 , Yick-Pang Ching 2 , Hiroshi Takemori 3 , Dong-Yan Jin 1 From 16th International Conference on Human Retroviruses: HTLV and Related Viruses Montreal, Canada. 26-30 June 2013 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 met- formin 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-induci- ble 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 prolifera- tion. 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 phos- phorylation-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-trans- formed 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). Authors’ details 1 Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong. 2 Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong. 3 Laboratory of Cell Signaling and Metabolism, National Institute of Biomedical Innovation, Osaka, Japan. Published: 7 January 2014 doi:10.1186/1742-4690-11-S1-P112 Cite this article as: Tang et al.: Metformin inhibits human T-cell leukemia virus type 1 transcription through activation of LKB1 and salt- inducible kinases. Retrovirology 2014 11(Suppl 1):P112. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit * Correspondence: [email protected] 1 Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong Full list of author information is available at the end of the article Tang et al. Retrovirology 2014, 11(Suppl 1):P112 http://www.retrovirology.com/content/11/S1/P112 © 2014 Tang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Transcript of Metformin inhibits human T-cell leukemia virus type 1 transcription through activation of LKB1 and...
POSTER PRESENTATION Open Access
Metformin inhibits human T-cell leukemiavirus type 1 transcription through activationof LKB1 and salt-inducible kinasesHei-Man V Tang1*, Wei-Wei Gao1, Ching-Ping Chan1, Yeung-Tung Siu1, Chi-Ming Wong1, Kin-Hang Kok1,Yick-Pang Ching2, Hiroshi Takemori3, Dong-Yan Jin1
From 16th International Conference on Human Retroviruses: HTLV and Related VirusesMontreal, Canada. 26-30 June 2013
Human T-cell leukemia virus type 1 (HTLV-1) causesadult T-cell leukemia (ATL). Specific therapeutic andprophylactic agents are not available. Epidemiologicalstudies have established a correlation between long-termuse of the commonly prescribed anti-diabetic drug met-formin and a decrease in the incidence of breast andother cancers. Whether metformin might also have anti-HTLV-1 and anti-ATL activity is unclear. In this studywe demonstrate an inhibitory effect of metformin onHTLV-1 transcription mediated through the activationof LKB1 tumor suppressor and downstream salt-induci-ble kinases (SIKs). Treatment of HTLV-1- transformedATL cells or cells transfected with HTLV-1 molecularclone pX1MT with metformin led to reduction in cell-free virion production and inhibition of cell prolifera-tion. This effect was attributed to the activation ofLKB1/SIK1 which compromised Tax expression andHTLV-1 transcription. LKB1 and SIKs function as hostrestriction factors that counteract Tax activation ofHTLV-1 long terminal repeats. Expression of LKB1 andactivated SIKs effectively blunted Tax activity in a phos-phorylation-dependent manner in LKB1-null HeLa cells,whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function inLKB1-proficient HEK293T cells. Activated LKB1 andSIKs associated with Tax. Enforced expression of LKB1or SIK1 in pX1MT-transfected cells and HTLV-1-trans-formed 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 anew negative regulatory function of LKB1 and SIKs inHTLV-1 transcription. (Supported by HKU7661/08M,HKU7674/12M, HKU1/CRF/11G and SKY-MRF-2011).
Authors’ details1Department of Biochemistry, The University of Hong Kong, Pokfulam,Hong Kong. 2Department of Anatomy, The University of Hong Kong,Pokfulam, Hong Kong. 3Laboratory of Cell Signaling and Metabolism,National Institute of Biomedical Innovation, Osaka, Japan.
Published: 7 January 2014
doi:10.1186/1742-4690-11-S1-P112Cite this article as: Tang et al.: Metformin inhibits human T-cellleukemia virus type 1 transcription through activation of LKB1 and salt-inducible kinases. Retrovirology 2014 11(Suppl 1):P112.
Submit your next manuscript to BioMed Centraland take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at www.biomedcentral.com/submit
* Correspondence: [email protected] of Biochemistry, The University of Hong Kong, Pokfulam,Hong KongFull list of author information is available at the end of the article
Tang et al. Retrovirology 2014, 11(Suppl 1):P112http://www.retrovirology.com/content/11/S1/P112
© 2014 Tang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
