Enhancement of mitomycin C-induced apoptosis in Nrf2-deficient human colon cancer cells
Tóm tắt
The nuclear erythroid factor 2-related factor 2 (Nrf2) is widely known as an important redox factor to protect cells from oxidative stress. However, recently it is known that Nrf2 in cancer cells provides advantages for cell viability from the exposure to anticancer drugs. Mitomycin C (MMC) is an anticancer drug for treatment of several types of cancers including colon and breast cancers. It is potent DNA crosslinker. MMC is able to induce ROS as part of its mechanism of action, which exerts detrimental effects to cancer cells. In this study, we investigated the role of Nrf2 in resistance to MMC in human colon cancer cells. Stable Nrf2 shRNA-expressing RKO showed higher sensitivity to MMC exposure than Nrf2 wild type cells. Furthermore, significantly increased apoptosis was associated with high level of oxidative stress and expression of DNA damage sensitive protein, phosphorylated H2AX (gamma-H2AX) in Nrf2 deficient human colon RKO cells. In conclusion, we demonstrated for the first time that Nrf2 enhanced MMCresistance via inhibition of oxidative stress and DNA damage in human colon cancer cells. Therefore, we suggested that Nrf2 might be potential therapeutic target in the MMC treatment of colon cancer.
Tài liệu tham khảo
Bradner, W. T. Mitomycin C: a clinical update. Cancer Treatment Reviews 27:35–50 (2001).
Tomasz, M. et al. Isolation and structure of a covalent cross-link adduct between mitomycin C and DNA. Science 235:1204–1208 (1987).
Komiyama, T. et al. Generation of hydroxyl radical by anticancer quinine drugs, carbazilquinone, mitomycin C, aclacinomycin A and adriamycin, in the presence of NADPH-cytochrome P-450 reductase. Biochem Pharmacol 31:3651–3656 (1982).
Butler, J. et al. Reactions of the semiquinone free radicals of anti-tumouragents with oxygen and iron complexes. FEBS Lett 182:95–98 (1985).
Park, H. K. et al. Mitomycin C-induced cell death in mouse lens epithelial cells. Ophthalmic Res 34:213–219 (2002).
Zhang, D. D. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev 38:769–789 (2006).
Venugopal, R. et al. Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H: quinone oxidoreductase1 gene. Proc Natl Acad Sci USA 93:14960–14965 (1996).
Ramos-Gomez, M. et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415 (2001).
Chan, K. et al. An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci USA 98:4611–4616 (2001).
Hu, X. et al. Accelerated ovarian failure induced by 4-vinyl cyclohexene diepoxide in Nrf2 null mice. Mol Cell Biol 26:940–954 (2006).
Alexandria, L. et al. Dual roles of Nrf2 in cancer. Pharmacological Research 58:262–270 (2008)
Jaiswal, A. K. Nrf2 signaling in coordinated activation of antioxidant gene expression. Free Radic Biol Med 36:1199–1207 (2004).
Hayashi, A. et al. Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochem Biophys Res Commun 310:824–829 (2003).
Vollrath, V. et al. Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem J 395:599–609 (2006).
Cho, J. M. et al. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: Implication to cancer cell resistance. Cancer Letters 260:96–108 (2008).
Grogan, T. M. et al. Thioredoxin, a putative oncogene product, is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival. Hum Pathol 31:475–481 (2000).
Soini, Y. et al. Widespread expression of thioredoxin and thioredoxin reductase in non-small cell lung carcinoma. Clin Cancer Res 7:1750–1757 (2001).
Lehtonen, S. T. et al. Variable overoxidation of peroxiredoxins in human lung cells in severe oxidative stress. Am J Physiol Lung Cell Mol Physiol 288:997–1001 (2005).
Wang, X. J. et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235–1243 (2008).
Homma, S. et al. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15:3423–3432 (2009).
Rotilio, G. et al. Biochemical mechanism of oxidative damage by redox-cycling drugs. Environ Health Perspect 64:259–264 (1985).
Akhdara, H. et al. Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. European Journal of Cancer 45:2219–2227 (2009).
Stacy, D. R. et al. Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck 28:813–818 (2006).