期刊
ONCOTARGET
卷 6, 期 28, 页码 26266-26277出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4656
关键词
LSF; HCC; FQI; mitotic arrest; apoptosis
资金
- James S. McDonnell Foundation
- National Cancer Institute [R01 CA138540-01A1]
- National Institutes of Health [R01 CA134721, R01 GM078240, P50 GM67041]
- Samuel Waxman Cancer Research Foundation (SWCRF)
- Johnson and Johnson Clinical Innovation Award
- Boston University Ignition Award
- Alnylam Pharmaceuticals, Inc.
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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