Skp2 Modulates Proliferation, Senescence and Tumorigenesis of Glioma

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2020 Mar 14

PMID 32165861

Citations 19

Authors

Juan Wu

Hong-Kai Su

Zhi-Hui Yu

Shao-Yan Xi

Cheng-Cheng Guo

Zhe-Yu Hu

Yue Qu

Hai-Ping Cai

Yi-Ying Zhao

Hua-Fu Zhao

Fu-Rong Chen

Yu-Fan Huang

Shing-Shun Tony To

Bing-Hong Feng

Ke Sai

Zhong-Ping Chen

Jing Wang

Affiliations

Soon will be listed here.

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.

Citing Articles

Raddeanin A (RA) Inhibited EMT and Stemness in Glioblastoma via downregulating Skp2.

Jia W, Zhang Y, Zhao Q, Gong M, Cao Y, Liu J J Cancer. 2025; 16(1):44-54.

PMID: 39744562 PMC: 11660117. DOI: 10.7150/jca.95266.

Targeting mitochondrial quality control: new therapeutic strategies for major diseases.

Hong W, Huang H, Zeng X, Duan C Mil Med Res. 2024; 11(1):59.

PMID: 39164792 PMC: 11337860. DOI: 10.1186/s40779-024-00556-1.

Identification of a miRNA multi-targeting therapeutic strategy in glioblastoma.

Bassot A, Dragic H, Haddad S, Moindrot L, Odouard S, Corlazzoli F Cell Death Dis. 2023; 14(9):630.

PMID: 37749143 PMC: 10519979. DOI: 10.1038/s41419-023-06117-z.

Cellular senescence in glioma.

Chojak R, Fares J, Petrosyan E, Lesniak M J Neurooncol. 2023; 164(1):11-29.

PMID: 37458855 DOI: 10.1007/s11060-023-04387-3.

Small-molecule compounds inhibiting S-phase kinase-associated protein 2: A review.

Jing J, Rui L, Junyuan S, Jinfeng Y, Zhihao H, Weiguo L Front Pharmacol. 2023; 14:1122008.

PMID: 37089937 PMC: 10113621. DOI: 10.3389/fphar.2023.1122008.

References

Seliger C, Hau P . Drug Repurposing of Metabolic Agents in Malignant Glioma. Int J Mol Sci. 2018; 19(9). PMC: 6164672. DOI: 10.3390/ijms19092768. View

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

Hu L, Ibrahim S, Liu C, Skaar J, Pagano M, Karpatkin S . Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222. Cancer Res. 2009; 69(8):3374-81. PMC: 2680713. DOI: 10.1158/0008-5472.CAN-08-4290. View

Chen Y, Li W, Zeng Z, Tang Y . (-)-Gochnatiolide B, synthesized from dehydrocostuslactone, exhibits potent anti-bladder cancer activity in vitro and in vivo. Sci Rep. 2018; 8(1):8807. PMC: 5995859. DOI: 10.1038/s41598-018-27036-6. View

Lee S, McCormick F . Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. J Mol Med (Berl). 2004; 83(4):296-307. DOI: 10.1007/s00109-004-0611-7. View

Chen V, Hsieh Y, Chen L, Hsu T, Tzang B . Escitalopram oxalate induces apoptosis in U-87MG cells and autophagy in GBM8401 cells. J Cell Mol Med. 2017; 22(2):1167-1178. PMC: 5783874. DOI: 10.1111/jcmm.13372. View

Jia T, Zhang L, Duan Y, Zhang M, Wang G, Zhang J . The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway. Cancer Cell Int. 2014; 14(1):126. PMC: 4272549. DOI: 10.1186/s12935-014-0126-4. View

Wei X, Li X, Yan W, Zhang X, Sun Y, Zhang F . SKP2 Promotes Hepatocellular Carcinoma Progression Through Nuclear AMPK-SKP2-CARM1 Signaling Transcriptionally Regulating Nutrient-Deprived Autophagy Induction. Cell Physiol Biochem. 2018; 47(6):2484-2497. DOI: 10.1159/000491622. View

Tsai Y, Kuo P, Kuo M, Hung W, Wu L, Chang W . The Interaction of miR-378i-Skp2 Regulates Cell Senescence in Diabetic Nephropathy. J Clin Med. 2018; 7(12). PMC: 6306775. DOI: 10.3390/jcm7120468. View

10.

. The 150 most important questions in cancer research and clinical oncology series: questions 94-101 : Edited by Cancer Communications. Cancer Commun (Lond). 2018; 38(1):69. PMC: 6257962. DOI: 10.1186/s40880-018-0341-9. View

11.

Wang L, Ye X, Cai X, Su J, Ma R, Yin X . Curcumin suppresses cell growth and invasion and induces apoptosis by down-regulation of Skp2 pathway in glioma cells. Oncotarget. 2015; 6(20):18027-37. PMC: 4627233. DOI: 10.18632/oncotarget.4090. View

12.

Yawata T, Higashi Y, Kawanishi Y, Nakajo T, Fukui N, Fukuda H . CD146 is highly expressed in glioma stem cells and acts as a cell cycle regulator. J Neurooncol. 2019; 144(1):21-32. DOI: 10.1007/s11060-019-03200-4. View

13.

Wang J, Han F, Wu J, Lee S, Chan C, Wu C . The role of Skp2 in hematopoietic stem cell quiescence, pool size, and self-renewal. Blood. 2011; 118(20):5429-38. PMC: 3217347. DOI: 10.1182/blood-2010-10-312785. View

14.

Byun W, Jin M, Yu J, Kim W, Song J, Chung H . A novel selenonucleoside suppresses tumor growth by targeting Skp2 degradation in paclitaxel-resistant prostate cancer. Biochem Pharmacol. 2018; 158:84-94. DOI: 10.1016/j.bcp.2018.10.002. View

15.

Huo J, Chen X, Zhang H, Hu Y, Jiang Y, Liu S . Bcl-3 promotes proliferation and chemosensitivity in BL1 subtype of TNBC cells. Acta Biochim Biophys Sin (Shanghai). 2018; 50(11):1141-1149. DOI: 10.1093/abbs/gmy117. View

16.

Bar E, Chaudhry A, Farah M, Eberhart C . Hedgehog signaling promotes medulloblastoma survival via Bc/II. Am J Pathol. 2007; 170(1):347-55. PMC: 1762704. DOI: 10.2353/ajpath.2007.060066. View

17.

Feng H, Wang J, Jiang H, Mei X, Zhao Y, Chen F . β-Elemene Selectively Inhibits the Proliferation of Glioma Stem-Like Cells Through the Downregulation of Notch1. Stem Cells Transl Med. 2017; 6(3):830-839. PMC: 5442766. DOI: 10.5966/sctm.2016-0009. View

18.

Ding L, Wang C, Cui Y, Han X, Zhou Y, Bai J . S-phase kinase-associated protein 2 is involved in epithelial-mesenchymal transition in methotrexate-resistant osteosarcoma cells. Int J Oncol. 2018; 52(6):1841-1852. PMC: 5919717. DOI: 10.3892/ijo.2018.4345. View

19.

Tang Z, Kang B, Li C, Chen T, Zhang Z . GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019; 47(W1):W556-W560. PMC: 6602440. DOI: 10.1093/nar/gkz430. View

20.

Wang J, Huang Y, Guan Z, Zhang J, Su H, Zhang W . E3-ligase Skp2 predicts poor prognosis and maintains cancer stem cell pool in nasopharyngeal carcinoma. Oncotarget. 2014; 5(14):5591-601. PMC: 4170633. DOI: 10.18632/oncotarget.2149. View