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Mus81 knockdown improves chemosensitivity of hepatocellular carcinoma cells by inducing S-phase arrest and promoting apoptosis through CHK1 pathway
- Source :
- Cancer Medicine
- Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
Apoptosis
Small hairpin RNA
Mice
0302 clinical medicine
Gene Knockdown Techniques
RNA, Small Interfering
Original Research
Cancer Biology
Mice, Knockout
Gene knockdown
Liver Neoplasms
hepatocellular carcinoma
Cell cycle
Tumor Burden
DNA-Binding Proteins
chemosensitivity
Oncology
cell cycle arrest
030220 oncology & carcinogenesis
S Phase Cell Cycle Checkpoints
Signal Transduction
Carcinoma, Hepatocellular
CHK1
Genetic Vectors
Antineoplastic Agents
Biology
03 medical and health sciences
Cell Line, Tumor
Animals
Humans
Radiology, Nuclear Medicine and imaging
MTT assay
Mus81
CHEK1
Protein Kinase Inhibitors
Epirubicin
Dose-Response Relationship, Drug
Lentivirus
Endonucleases
Xenograft Model Antitumor Assays
digestive system diseases
Disease Models, Animal
030104 developmental biology
Cell culture
Drug Resistance, Neoplasm
Immunology
Checkpoint Kinase 1
Cancer research
Protein Kinases
Subjects
Details
- ISSN :
- 20457634
- Volume :
- 5
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cancer medicine
- Accession number :
- edsair.doi.dedup.....b9b3834d9cc06550ebecb21a2af5a45e