Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): evaluation using an endogenous HCC model
Date
2015-09-22
Authors
Rajasekaran, Devaraja
Siddiq, Ayesha
Willoughby, Jennifer L. S.
Biagi, Jessica M.
Christadore, Lisa M.
Yunes, Sarah A.
Gredler, Rachel
Jariwala, Nidhi
Robertson, Chadia L.
Akiel, Maaged A.
Version
Published version
OA Version
Citation
Devaraja Rajasekaran, Ayesha Siddiq, Jennifer LS 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, Devanand Sarkar. 2015. "Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model." ONCOTARGET, Volume 6, Issue 28, pp. 26266 - 26277 (12). https://doi.org/10.18632/oncotarget.4656
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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This article is made available under a Creative Commons Attribution 3.0 License.