title: ISG15 inhibits cancer cell growth and promotes apoptosis.
abstract: Cervical cancer is one of the most common causes of cancer-related mortality in women in developing countries. Interferon (IFN)-α has been widely used in the treatment of various types of cancer, including cervical cancer, and IFN-stimulated gene 15 (ISG15), an ubiquitin-like protein, is upregulated by IFN-α treatment. The anti-virus and antitumor effects of ISG15 have been reported; however, its mechanism of action have not yet been fully elucidated. In this study, HeLa cells were used as a model system to investigate the roles of ISG15 in IFN-α-mediated cancer cell growth inhibition and induction of apoptosis. The results revealed that both p53 and p21 were upregulated in HeLa cells treated with IFN-α or in the HeLa cells overexpressing ISG15. In addition, the expression levels of ubiquitin-like modifier-activating enzyme 7 (UBA7, also known as UBE1L; ISG15 E1-activating enzyme), UBCH8 (ISG15 E2-conjugating enzyme) and HERC5 (ISG15 E3-ligase) were elevated in the HeLa cells treated with IFN-α. The levels of p53 in the HeLa cells were attenuated by transient transfection with small interfering RNA (siRNA) targeting ISG15 (ISG15-siRNA). Cell viability was inhibited by both IFN-α treatment and ISG15 overexpression. However, these effects were significantly diminished when p53 was knocked down, suggesting that the effects of inhibitory effects of ISG15 on HeLa cell growth and the induction of apoptosis were p53-dependent. Taken together, these results suggest the existence of the IFN-α/ISG15/p53 axis in cervical cancer cells and any strategies manipulating the levels of ISG15 may thus prove to be effective in the treatment of cervical cancer.
authors.affiliation: Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Zhou
authors.affiliation: Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, P.R. China.
authors.forename: Fang-Zhi
authors.initials: FZ
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Han-Chun
authors.initials: HC
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xin-Xing
authors.initials: XX
authors.lastname: Wan
authors.affiliation: Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Fang
authors.affiliation: Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
authors.forename: Dian-Zheng
authors.initials: DZ
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015415:Biomarkers; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000235:genetics*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics*
chemical_list: D015415:Biomarkers; D016207:Cytokines; C402395:HERC5 protein, human; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C074034:ISG15 protein, human; D053148:Caspase 3; D044764:Ubiquitin-Activating Enzymes