Oncotarget

Research Papers:

Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model

Devaraja Rajasekaran, Ayesha Siddiq, Jennifer L.S. Willoughby, Jessica M. Biagi, Lisa M. Christadore, Sarah A. Yunes, Rachel Gredler, Nidhi Jariwala, Chadia L. Robertson, Maaged A. Akiel, Xue-Ning Shen, Mark A. Subler, Jolene J. Windle, Scott E. Schaus, Paul B. Fisher, Ulla Hansen and Devanand Sarkar _

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Oncotarget. 2015; 6:26266-26277. https://doi.org/10.18632/oncotarget.4656

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Abstract

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

Correspondence to:

Devanand Sarkar, e-mail: dsarkar@vcu.edu

Keywords: LSF, HCC, FQI, mitotic arrest, apoptosis

Received: March 09, 2015     Accepted: July 06, 2015     Published: July 17, 2015

ABSTRACT

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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