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.

Erianin inhibits human cervical cancer cell through regulation of tumor protein p53 via the extracellular signal‑regulated kinase signaling pathway

“…Previous studies confirmed that p53 was one of the most commonly mutation genes in cancer ( 30 – 32 ). Additionally, the upregulation of p53 in cancer cells may prevent cancer cell proliferation by promoting cell cycle arrest and apoptosis ( 33 – 36 ). Liu et al ( 37 ) revealed that the p53 pathway in human cervical cancer cells is activated by reversion-inducing-cysteine-rich protein with Kazal motifs overexpression, which induces cancer cell apoptosis and reduces migration.…”

Regulation of the Tumor-Suppressor BECLIN 1 by Distinct Ubiquitination Cascades

“…In general, ISG15 is involved in anti-viral pathways and ISG15-deficient mice are highly susceptible for viral infections like herpes or influenza [ 170 , 171 ]. In general, ISG15 is an important type I interferon (IFN) effector system.…”

Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

“…The result showed the statistically most significant differences in cell cycle and apoptosis. Previous reports found that (Zhou et al, 2017;Park et al, 2000;Smith, 2015;Yang et al, 1997) Il2, Bcl2, Stat2, Isg15, Oasl2 may participate in the cell survival and anti-apoptosis processes, and these genes were found to be quantitatively different in the culture with B6 DCs and IL-2-deficient DCs by real time PCR (Fig. 5D).…”