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.
Highlights
Hepatocellular carcinoma (HCC) is one of the five most common malignancies and the third leading cause of cancer related deaths worldwide [1]
In the present study we report the chemotherapeutic efficacy of Late SV40 Factor (LSF) inhibitors on DEN-induced HCC in Alb/c-myc transgenic mice
We previously documented that the Factor Quinolinone Inhibitor 1 (FQI1) inhibits human HCC xenografts in a nude mouse model [12]
Summary
Hepatocellular carcinoma (HCC) is one of the five most common malignancies and the third leading cause of cancer related deaths worldwide [1]. Despite a decline in overall cancer incidence, there is a steady increase in the incidence of HCC, especially in the US [2]. This problem is compounded by the fact that HCC is a disease with very poor prognosis with only 10% of patients having 5 year mean survival rate using currently available treatments [3]. The only FDA-approved drug, sorafenib, for non-resectable HCC provides a survival benefit of www.impactjournals.com/oncotarget only 2.8 months [4]. As such there is an urgent need for developing new molecular targeted therapy for HCC. Nuclear translocation of LSF upon overexpression of Snail can lead to transcriptional upregulation of fibronectin expression, contributing to induction of the epithelial-mesenchymal transition (EMT) [11]
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