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Silencing thioredoxin induces liver cancer cell senescence under hypoxia
Author(s) -
Zhang Ti,
Liu Heping,
Zhu Cihui,
Briggs Katrina,
Kang Ya'an,
Fleming Jason A.,
Curley Steven A.
Publication year - 2012
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2012.00973.x
Subject(s) - cell growth , dna damage , biology , microbiology and biotechnology , senescence , thioredoxin , apoptosis , gene silencing , cancer research , hypoxia (environmental) , cell cycle , flow cytometry , cell , cell culture , chemistry , biochemistry , oxidative stress , dna , genetics , organic chemistry , oxygen , gene
Aim: Although thioredoxin 1 (TXN) has pleiotropic cellular functions as a redox‐sensitive protein, very little is known about its role in tumor survival and growth under hypoxia. MHCC97H hepatocellular carcinoma cells have a high metastatic potential and high thioredoxin expression levels compared with their parent cell line, MHCC97. Thus, we used this cell line to explore the functional connections between TXN and hypoxia. Methods: MHCC97H cells were cultured under normoxia and hypoxia for specific periods after nucleofection with TXN siRNA or control siRNA. We assessed the β‐phenylethyl isothiocyanate (PEITC) sensitivity of the cells, cell proliferation, cell cycle and senescence, and DNA damage response by using 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays, colony formation assays, flow cytometry, β‐galactosidase staining, western blotting, and immunohistochemistry. Results: β‐phenylethyl isothiocyanate treatment shifted reduced TXN to oxidized TXN in MHCC97H cells. Although silencing of TXN via siRNA had no effect on the PEITC sensitivity of the cells, it suppressed cell proliferation and colony formation under both normoxia and hypoxia. Under hypoxia, silencing TXN did not induce apoptosis but induced DNA damage response and cellular senescence. Conclusions: High TXN levels in MHCC97H cells protect them from DNA damage and cellular senescence under hypoxia. Targeting TXN might enhance the chemotherapeutic effects of some DNA‐damaging agents against hepatocellular carcinoma.