Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway.

Publisher: John Wiley & Sons Ltd Country of Publication: United States NLM ID: 101595310 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2045-7634 (Electronic) Linking ISSN: 20457634 NLM ISO Abbreviation: Cancer Med Subsets: MEDLINE

Original Publication: [Malden, MA] : John Wiley & Sons Ltd., c2012-

Signal Transduction*; Apoptosis/*genetics ; Carcinoma, Hepatocellular/*genetics ; Carcinoma, Hepatocellular/*metabolism ; DNA-Binding Proteins/*genetics ; Endonucleases/*genetics ; Liver Neoplasms/*genetics ; Liver Neoplasms/*metabolism ; Protein Kinases/*metabolism ; S Phase Cell Cycle Checkpoints/*genetics; Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Cell Line, Tumor ; Checkpoint Kinase 1 ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/genetics ; Epirubicin/pharmacology ; Gene Knockdown Techniques ; Genetic Vectors/genetics ; Humans ; Lentivirus/genetics ; Mice ; Mice, Knockout ; Protein Kinase Inhibitors/pharmacology ; RNA, Small Interfering/genetics ; S Phase Cell Cycle Checkpoints/drug effects ; Tumor Burden ; Xenograft Model Antitumor Assays

As a critical endonuclease in DNA repair, Mus81 is traditionally regarded as a tumor suppressor, but recently correlated with the sensitivity of mitomycin C and 5-fluorouracil in colon cancer and breast cancer cells. However, its role in chemosensitivity of other human malignancies still remains unknown. This study therefore aims to investigate the effects of Mus81 knockdown on the chemosensitivity of hepatocellular carcinoma (HCC), a usually chemorefractory tumor, and explore the underlying mechanisms. Mus81 expression in HepG2 and Bel-7402 HCC cell lines was depleted by lentivirus-mediated short hairpin RNA and the elevated sensitivity of these Mus81-inhibited HCC cells to therapeutic agents, especially to epirubicin (EPI), was evidenced by MTT assay and an HCC chemotherapy mouse model. Flow cytometric analysis also showed that Mus81 knockdown lead to an obvious S-phase arrest and an elevated apoptosis in EPI-treated HepG2 and Bel-7402 cells, which could be rescued by CHK1 inhibition. The activation of CHK1/CDC25A/CDK2 pathway was also demonstrated in Mus81-inhibited HepG2 cells and xenograft mouse tumors under EPI treatment. Meanwhile, the apoptosis of HepG2 cells in response to EPI was remarkably promoted by Mus81 knockdown through activating p53/Bax/Caspase-3 pathway under the controlling of CHK1. In addition, CHK2 inhibition slightly raised CHK1 activity, thereby enhancing the S-phase arrest and apoptosis induced by EPI in Mus81-suppressed HCC cells. In conclusion, Mus81 knockdown improves the chemosensitivity of HCC cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway, suggesting Mus81 as a novel therapeutic target for HCC.
(© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Mol Cancer Ther. 2014 Aug;13(8):2062-72. (PMID: 24867249)
PLoS One. 2014 Mar 04;9(3):e90358. (PMID: 24595063)
Lancet. 2012 Mar 31;379(9822):1245-55. (PMID: 22353262)
PLoS One. 2012;7(8):e44021. (PMID: 22937147)
Genes Cells. 2005 Feb;10(2):97-106. (PMID: 15676021)
Onco Targets Ther. 2014 Oct 21;7:1883-90. (PMID: 25364260)
Nucleic Acids Res. 2015 Apr 20;43(7):3626-42. (PMID: 25765656)
Mol Biol Cell. 2008 Feb;19(2):445-56. (PMID: 18032583)
Eur J Pharmacol. 2011 Nov 30;670(2-3):356-64. (PMID: 21958871)
Biochem Pharmacol. 2009 Mar 1;77(5):770-80. (PMID: 19059218)
PLoS One. 2012;7(1):e29783. (PMID: 22279545)
World J Hepatol. 2015 Apr 18;7(5):787-98. (PMID: 25914779)
PLoS One. 2015 Apr 15;10(4):e0123333. (PMID: 25875766)
PLoS Genet. 2011 May;7(5):e1001385. (PMID: 21625617)
PLoS One. 2015 Apr 02;10(3):e0120574. (PMID: 25837669)
Science. 2004 Jun 18;304(5678):1822-6. (PMID: 15205536)
Biochem Biophys Res Commun. 2014 Jun 6;448(3):248-54. (PMID: 24792179)
CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90. (PMID: 21296855)
PLoS One. 2011;6(8):e23517. (PMID: 21858151)
Mol Cell Biol. 2005 Sep;25(17):7569-79. (PMID: 16107704)
Cancer Treat Rev. 2011 May;37(3):212-20. (PMID: 20724077)
Cancer Sci. 2011 Feb;102(2):472-7. (PMID: 21175991)
Anticancer Res. 2010 Dec;30(12):5011-4. (PMID: 21187482)
Int J Cancer. 2009 Jun 15;124(12):2997-3001. (PMID: 19267403)
Cancer Med. 2016 Feb;5(2):370-85. (PMID: 26714930)
J Hepatol. 2012 Mar;56(3):686-95. (PMID: 21971559)
Cell Cycle. 2008 Jun 1;7(11):1668-77. (PMID: 18469532)
Nat Commun. 2015 Apr 16;6:6746. (PMID: 25879486)
Oncotarget. 2015 May 10;6(13):11547-60. (PMID: 25909168)
Cancer. 2008 May 1;112(9):2002-10. (PMID: 18327812)
Cancer Res. 2007 Sep 15;67(18):8527-35. (PMID: 17875692)
Gut. 2014 May;63(5):844-55. (PMID: 24531850)
Cancer. 2014 Sep 15;120(18):2824-38. (PMID: 24897995)
BMC Cancer. 2014 Dec 19;14:987. (PMID: 25527123)
Nan Fang Yi Ke Da Xue Xue Bao. 2014 Dec;34(12):1776-9. (PMID: 25537901)
Asian Pac J Cancer Prev. 2014;15(8):3651-7. (PMID: 24870773)
Nucleic Acids Res. 2006 Feb 02;34(3):880-92. (PMID: 16456034)

Keywords: Apoptosis; CHK1; Mus81; cell cycle arrest; chemosensitivity; hepatocellular carcinoma

0 (Antineoplastic Agents)
0 (DNA-Binding Proteins)
0 (Protein Kinase Inhibitors)
0 (RNA, Small Interfering)
3Z8479ZZ5X (Epirubicin)
EC 2.7.- (Protein Kinases)
EC 2.7.11.1 (CHEK1 protein, human)
EC 2.7.11.1 (Checkpoint Kinase 1)
EC 2.7.11.1 (Chek1 protein, mouse)
EC 3.1.- (Endonucleases)
EC 3.1.- (Mus81 protein, mouse)

Date Created: 20151231 Date Completed: 20161020 Latest Revision: 20210109

20250114

PMC4735774

10.1002/cam4.588

26714930