Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model
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 xe...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694900/ https://www.ncbi.nlm.nih.gov/pubmed/26313006 |
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author | 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. Shen, Xue-Ning Subler, Mark A. Windle, Jolene J. Schaus, Scott E. Fisher, Paul B. Hansen, Ulla Sarkar, Devanand |
author_facet | 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. Shen, Xue-Ning Subler, Mark A. Windle, Jolene J. Schaus, Scott E. Fisher, Paul B. Hansen, Ulla Sarkar, Devanand |
author_sort | Rajasekaran, Devaraja |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4694900 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-46949002016-01-20 Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model 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. Shen, Xue-Ning Subler, Mark A. Windle, Jolene J. Schaus, Scott E. Fisher, Paul B. Hansen, Ulla Sarkar, Devanand Oncotarget Research Paper 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. Impact Journals LLC 2015-07-17 /pmc/articles/PMC4694900/ /pubmed/26313006 Text en Copyright: © 2015 Rajasekaran et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper 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. Shen, Xue-Ning Subler, Mark A. Windle, Jolene J. Schaus, Scott E. Fisher, Paul B. Hansen, Ulla Sarkar, Devanand Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model |
title | Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model |
title_full | Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model |
title_fullStr | Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model |
title_full_unstemmed | Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model |
title_short | Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model |
title_sort | small molecule inhibitors of late sv40 factor (lsf) abrogate hepatocellular carcinoma (hcc): evaluation using an endogenous hcc model |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694900/ https://www.ncbi.nlm.nih.gov/pubmed/26313006 |
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