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STAT3 & Cytochrome P450 2C9: A novel signaling pathway in liver cancer stem cells
Cited 12 time in
Web of Science
Cited 14 time in Scopus
- Authors
- Issue Date
- 2012-12
- Publisher
- ELSEVIER
- Citation
- BIOMEDICINE & PHARMACOTHERAPY Vol.66 No.8, pp. 612-616
- Keywords
- 복합학 ; Cancer stem cell ; Cytochrome P450 epoxygenase 2C9 ; inhibitor ; STAT3 ; Hypoxia
- Abstract
- Although cancer stem cells (CSCs) are believed to be the key drivers in tumor growth and resistance to
therapy, the specific signaling of CSCs is largely unknown. In this study, we evaluated the roles of hypoxia
and STAT3 signaling on the treatment resistance of CSCs. Side population (SP) cell analysis and sorting
were used to detect subpopulations that function as CSCs. Huh-7 cells, doxorubicin, sulfaphenazole (a
CYP2C9 inhibitor), and AG490 (a STAT3 inhibitor) were used in this study. Cell growth and apoptosis
were assessed using MTS assays, and apoptotic and kinase signaling pathways were explored by
immunoblotting. Treatment with IL-6 induced STAT3 activation more significantly in SP than non-SP
cells. Hypoxia induced SP cell proliferation, and microarray analysis showed that the expression of
CYP2C9 was significantly increased in hypoxic than normoxic SP cells. Although hypoxic SP cells were
less sensitive to doxorubicin-induced apoptosis, pretreatment with sulfaphenazole sensitized hypoxic
SP cells to doxorubicin cytotoxicity. These results indicate that STAT3 is critical for CSC survival and
hypoxia-inducible CYP2C9 expression is responsible the doxorubicin resistance of CSCs under hypoxic
conditions. Thus, the selective inhibition of CYP2C9 and STAT3 may be implicated in the sensitization of
CSCs to anti-cancer treatment, particularly in advanced cases.
- ISSN
- 0753-3322
- Language
- English
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