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ISG15 inhibits cancer cell growth and promotes apoptosis
Mei-Juan Zhou1, Fang-Zhi Chen2, Han-Chun Chen1
1Department of Biochemistry, School of Life Sciences and the State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410013, P.R. China.
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.
Insights
Interferon-alpha (IFN-α) upregulates ISG15, inhibiting cervical cancer cell growth and promoting apoptosis. This IFN-α/ISG15/p53 pathway is crucial for their anti-cancer effects, suggesting ISG15 manipulation as a potential treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cervical cancer poses a significant mortality risk, particularly in developing nations.
- Interferon-alpha (IFN-α) is a known therapeutic agent for various cancers, including cervical cancer.
- Interferon-stimulated gene 15 (ISG15) is upregulated by IFN-α and exhibits anti-viral and anti-tumor properties, though its precise mechanism remains unclear.
Purpose of the Study:
- To investigate the role of ISG15 in IFN-α-mediated growth inhibition and apoptosis in cervical cancer cells.
- To elucidate the molecular mechanisms underlying ISG15's function in the context of IFN-α treatment.
- To explore the potential of targeting the IFN-α/ISG15 pathway for cervical cancer therapy.
Main Methods:
- Utilized HeLa cells as a model system for cervical cancer.
- Analyzed the expression of p53, p21, and ISG15-related enzymes (UBA7, UBCH8, HERC5) following IFN-α treatment or ISG15 overexpression.
- Employed small interfering RNA (siRNA) to knockdown ISG15 and p53 expression.
- Assessed cell viability and apoptosis induction.
Main Results:
- IFN-α treatment and ISG15 overexpression upregulated both p53 and p21 in HeLa cells.
- Expression of UBA7, UBCH8, and HERC5 was elevated upon IFN-α treatment.
- ISG15 knockdown attenuated p53 levels.
- Both IFN-α treatment and ISG15 overexpression inhibited cell viability, but these effects were diminished upon p53 knockdown.
- Apoptosis induction by ISG15 was found to be p53-dependent.
Conclusions:
- Established the existence of an IFN-α/ISG15/p53 signaling axis in cervical cancer cells.
- Demonstrated that ISG15's inhibitory effects on HeLa cell growth and its role in apoptosis induction are mediated through a p53-dependent mechanism.
- Suggests that therapeutic strategies targeting ISG15 levels could be effective for treating cervical cancer.
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