Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model
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Devaraja Rajasekaran1, Ayesha Siddiq1, Jennifer L.S. Willoughby2,5, Jessica M. Biagi3, Lisa M. Christadore3, Sarah A. Yunes4, Rachel Gredler1, Nidhi Jariwala1, Chadia L. Robertson1, Maaged A. Akiel1, Xue-Ning Shen1, Mark A. Subler1, Jolene J. Windle1, Scott E. Schaus3, Paul B. Fisher1,6,7, Ulla Hansen2,4, Devanand Sarkar1,6,7
1Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA
2Department of Biology, Center for Chemical Methodology and Library Development at Boston University, Boston MA 02215
3Department of Chemistry, Center for Chemical Methodology and Library Development at Boston University, Boston MA 02215
4Program in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston MA 02215
5Alnylam Pharmaceuticals, Inc., Cambridge MA 02142
6Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
7VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
Devanand Sarkar, e-mail: [email protected]
Keywords: LSF, HCC, FQI, mitotic arrest, apoptosis
Received: March 09, 2015 Accepted: July 06, 2015 Published: July 17, 2015
Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality and poor prognosis. Oncogenic transcription factor Late SV40 Factor (LSF) plays an important role in promoting HCC. A small molecule inhibitor of LSF, Factor Quinolinone Inhibitor 1 (FQI1), significantly inhibited human HCC xenografts in nude mice without harming normal cells. Here we evaluated the efficacy of FQI1 and another inhibitor, FQI2, in inhibiting endogenous hepatocarcinogenesis. HCC was induced in a transgenic mouse with hepatocyte-specific overexpression of c-myc (Alb/c-myc) by injecting N-nitrosodiethylamine (DEN) followed by FQI1 or FQI2 treatment after tumor development. LSF inhibitors markedly decreased tumor burden in Alb/c-myc mice with a corresponding decrease in proliferation and angiogenesis. Interestingly, in vitro treatment of human HCC cells with LSF inhibitors resulted in mitotic arrest with an accompanying increase in CyclinB1. Inhibition of CyclinB1 induction by Cycloheximide or CDK1 activity by Roscovitine significantly prevented FQI-induced mitotic arrest. A significant induction of apoptosis was also observed upon treatment with FQI. These effects of LSF inhibition, mitotic arrest and induction of apoptosis by FQI1s provide multiple avenues by which these inhibitors eliminate HCC cells. LSF inhibitors might be highly potent and effective therapeutics for HCC either alone or in combination with currently existing therapies.
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