Skp2 modulates proliferation, senescence and tumorigenesis of glioma

Abstract

Background: Gliomas represent the largest class of primary central nervous system neoplasms, many subtypes of which exhibit poor prognoses. Surgery followed by radiotherapy and chemotherapy has been used as a standard strategy but yielded unsatisfactory improvements in patient survival outcomes. The S-phase kinase protein 2 (Skp2), a critical component of the E3-ligase SCF complex, has been documented in tumorigenesis in various cancer types but its role in glioma has yet to be fully clarified. In this study, we investigated the function of Skp2 in the proliferation, stem cell maintenance, and drug sensitivity to temozolomide (TMZ) of glioma. Methods:To investigate the role of Skp2 in the prognosis of patients with glioma, we first analyzed data in databases TCGA and GTEx. To further clarify the effect of Skp2 on glioma cell proliferation, we suppressed its level in glioblastoma (GBM) cell lines through knockdown and small molecule inhibitors (lovastatin and SZL-P1-41). We then detected cell growth, colony formation, sphere formation, drug sensitivity, and in vivo tumor formation in xenograft mice model.Results: Skp2 mRNA level was higher in both low-grade glioma and GBM than normal brain tissues. The knockdown of Skp2 increased cell sensitivity to TMZ, decreased cell proliferation and tumorigenesis. In addition, Skp2 level was found increased upon stem cells enriching, while the knockdown of Skp2 led to reduced sphere numbers. Downregulation of Skp2 also induced senescence. Repurposing of lovastatin and novel compound SZL-P1-41 suppressed Skp2 effectively, and enhanced glioma cell sensitivity to TMZ in vitro and in vivo. Conclusion:Our data demonstrated that Skp2 modulated glioma cell proliferation in vitro and in vivo, stem cell maintenance, and cell sensitivity to TMZ, which indicated that Skp2 could be a potential target for long-term treatment.

An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma

“…Statins are widely used agents with well-established toxicity profiles and pleiotropic effects that include potential antineoplastic action [ 75 , 76 , 77 , 78 , 168 ]. Statins were found to interfere with c-Myc through microRNA (miRNA) targeting [ 76 ].…”

“…Consistent with this, in medulloblastoma, lovastatin was found to increase miR-33b, resulting in inhibition of c-Myc [ 76 ]. In GBM, lovastatin was found to inhibit S-phase kinase protein (Skp2), an E3 ligase involved in tumorigenesis, and when combined with TMZ increased degradation of Skp2 in cells and xenografts [ 75 ]. Simvastatin was found to inhibit EGFR, fibroblast growth factor receptor (FGFR) and proto-oncogene tyrosine-kinase Src (c-SRC) [ 77 ], TKs that are highly active in GBM.…”

Therapeutic Potential of Curcumin for the Treatment of Malignant Gliomas

“…S-phase kinase protein 2 (Skp2) is a component of the SKP-Cullin-F box complex, which facilitates the ubiquitin-mediated degradation of G1 checkpoint inhibitors G21, P21 and P27; the net effect is cellular proliferation via cell cycle progression (31,32). Taking this into consideration, Skp2 overexpression results in unchecked cell cycle progression and has been associated with tumorigenesis, including gliomas (33)(34)(35).…”

Antitumor Activity of Curcumin in Glioblastoma

“…S-phase kinase protein 2 (Skp2), is a component of the Skp2-SCF E3 ligase complex, involved in conjugation of K48-linked ubiquitin chains to induce proteasome-mediated proteolysis, and conjugation of K63-linked ubiquitin chains to modulate substrate function [ 31 ]. Skp2 also forms the Skp-Cullin-F box complex, which is responsible for ubiquitin-mediated degradation of the G1 checkpoint CDK inhibitors, G21, P21 and P27, resulting in cell cycle progression [ 32 , 33 ]. Skp2 overexpression has been implicated in tumorigenesis and has been associated with multiple human cancers, including gliomas [ 31 , 34 , 35 ].…”

“…Skp2 overexpression has been implicated in tumorigenesis and has been associated with multiple human cancers, including gliomas [ 31 , 34 , 35 ]. Knockdown of Skp2 has been shown to increase sensitivity of gliomas to TMZ, attenuate growth of glioma cells and induce senescence in glioma cells [ 33 ]. U251 and SNB19 human GBM cells treated with variable curcumin preparations were found to have decreased Skp2 expression via RT-PCR, as well as decreased migration, invasion, and proliferation; viral transfection with Skp2 cDNA rescued growth inhibition by curcumin [ 36 ].…”