Paeoniflorin Exerts Antitumor Effects by Inactivating S Phase Kinase-associated Protein 2 in Glioma Cells

Overview

Journal Oncol Rep

Specialty Oncology

Date 2017 Dec 30

PMID 29286139

Citations 9

Authors

Jia Ouyang

Hui Xu

Ming Li

Xingliang Dai

Fengqing Fu

Xueguang Zhang

Qing Lan

Affiliations

Soon will be listed here.

Abstract

Paeoniflorin (PF), a natural compound isolated from Paeoniae radix, has been shown to exert antitumor effects in various types of human cancers including glioma. However, the mechanism of action is not well understood. S-phase kinase-associated protein (Skp)2 functions as an oncogene in many cancers. In the present study, we investigated whether Skp2 mediates the anti-glioma activity of PF. We found that PF inhibited glioma cell proliferation, migration and invasion, and induced G2/M arrest and apoptosis. Skp2 expression was downregulated in glioma cells treated with PF. PF-induced antitumor effects in glioma cells were abolished by Skp2 overexpression but were enhanced by RNA interference of Skp2. Moreover, PF treatment inhibited U87 cell-derived tumor growth in a xenograft mouse model. These results demonstrate that PF exerts its antitumor effects in part by inhibiting Skp2 expression in glioma cells and could be a promising therapeutic agent for glioma therapy.

Citing Articles

The Small Molecules of Plant Origin with Anti-Glioma Activity.

Liu X, Su Y, Yang Y, Li R, Zhang Z Int J Mol Sci. 2025; 26(5).

PMID: 40076568 PMC: 11900624. DOI: 10.3390/ijms26051942.

Paeonia genus: a systematic review of active ingredients, pharmacological effects and mechanisms, and clinical applications for the treatment of cancer.

Zhou X, Alimu A, Zhao J, Xu X, Li X, Lin H Arch Pharm Res. 2024; 47(8-9):677-695.

PMID: 39306813 DOI: 10.1007/s12272-024-01512-2.

Mechanisms of paeoniaceae action as an antidepressant.

Guo W, Yao X, Cui R, Yang W, Wang L Front Pharmacol. 2023; 13:934199.

PMID: 36844911 PMC: 9944447. DOI: 10.3389/fphar.2022.934199.

Paeoniflorin Regulates NEDD4L/STAT3 Pathway to Induce Ferroptosis in Human Glioma Cells.

Nie X, Qiu S, Xing Y, Xu J, Lu B, Zhao S J Oncol. 2023; 2022:6093216.

PMID: 36618071 PMC: 9812627. DOI: 10.1155/2022/6093216.

Paeoniflorin ameliorates glycemic variability-induced oxidative stress and platelet activation in HUVECs and DM rats.

Huang Y, Wang J, Yang L, Yue L, Zhang L, Zhang Y RSC Adv. 2022; 10(69):42605-42612.

PMID: 35692727 PMC: 9119283. DOI: 10.1039/d0ra02036b.

References

Lin H, Chen Z, Wang G, Nardella C, Lee S, Chan C . Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature. 2010; 464(7287):374-9. PMC: 2928066. DOI: 10.1038/nature08815. View

Chen G, Cheng Y, Zhang Z, Martinka M, Li G . Cytoplasmic Skp2 expression is increased in human melanoma and correlated with patient survival. PLoS One. 2011; 6(2):e17578. PMC: 3046256. DOI: 10.1371/journal.pone.0017578. View

Nie X, Ou-Yang J, Xing Y, Li D, Dong X, Liu R . Paeoniflorin inhibits human glioma cells via STAT3 degradation by the ubiquitin-proteasome pathway. Drug Des Devel Ther. 2015; 9:5611-22. PMC: 4610779. DOI: 10.2147/DDDT.S93912. View

Chen J, Li Y, Yu T, McKay R, Burns D, Kernie S . A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012; 488(7412):522-6. PMC: 3427400. DOI: 10.1038/nature11287. View

Nagahama H, Minamishima Y, Matsumoto M, Nakamichi I, Kitagawa K, Shirane M . Targeted disruption of Skp2 results in accumulation of cyclin E and p27(Kip1), polyploidy and centrosome overduplication. EMBO J. 2000; 19(9):2069-81. PMC: 305685. DOI: 10.1093/emboj/19.9.2069. View

Lin H, Wang G, Chen Z, Teruya-Feldstein J, Liu Y, Chan C . Phosphorylation-dependent regulation of cytosolic localization and oncogenic function of Skp2 by Akt/PKB. Nat Cell Biol. 2009; 11(4):420-32. PMC: 2830812. DOI: 10.1038/ncb1849. View

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

Fine H . New strategies in glioblastoma: exploiting the new biology. Clin Cancer Res. 2015; 21(9):1984-8. DOI: 10.1158/1078-0432.CCR-14-1328. View

Hung W, Tseng W, Shiea J, Chang H . Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 2009; 288(2):156-61. DOI: 10.1016/j.canlet.2009.06.032. View

10.

Chen T, Fu L, Zhang L, Yin B, Zhou P, Cao N . Paeoniflorin suppresses inflammatory response in imiquimod-induced psoriasis-like mice and peripheral blood mononuclear cells (PBMCs) from psoriasis patients. Can J Physiol Pharmacol. 2016; 94(8):888-94. DOI: 10.1139/cjpp-2015-0483. View

11.

Walbert T, Chasteen K . Palliative and supportive care for glioma patients. Cancer Treat Res. 2014; 163:171-84. DOI: 10.1007/978-3-319-12048-5_11. View

12.

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

13.

Lu J, He W, Song S, Wei W . Paeoniflorin inhibited the tumor invasion and metastasis in human hepatocellular carcinoma cells. Bratisl Lek Listy. 2014; 115(7):427-33. DOI: 10.4149/bll_2014_084. View

14.

Ma Z, Chu L, Liu H, Wang W, Li J, Yao W . Beneficial effects of paeoniflorin on non-alcoholic fatty liver disease induced by high-fat diet in rats. Sci Rep. 2017; 7:44819. PMC: 5353673. DOI: 10.1038/srep44819. View

15.

Wei Z, Jiang X, Qiao H, Zhai B, Zhang L, Zhang Q . STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. Cell Signal. 2013; 25(4):931-8. DOI: 10.1016/j.cellsig.2013.01.011. View

16.

He X, Xing D, Ding Y, Li Y, Xiang L, Wang W . Determination of paeoniflorin in rat hippocampus by high-performance liquid chromatography after intravenous administration of Paeoniae Radix extract. J Chromatogr B Analyt Technol Biomed Life Sci. 2004; 802(2):277-81. DOI: 10.1016/j.jchromb.2003.11.040. View

17.

Frescas D, Pagano M . Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer. 2008; 8(6):438-49. PMC: 2711846. DOI: 10.1038/nrc2396. View

18.

Ostrom Q, Bauchet L, Davis F, Deltour I, Fisher J, Langer C . The epidemiology of glioma in adults: a "state of the science" review. Neuro Oncol. 2014; 16(7):896-913. PMC: 4057143. DOI: 10.1093/neuonc/nou087. View

19.

He D, Dai S . Anti-inflammatory and immunomodulatory effects of paeonia lactiflora pall., a traditional chinese herbal medicine. Front Pharmacol. 2011; 2:10. PMC: 3108611. DOI: 10.3389/fphar.2011.00010. View

20.

Wu L, Wang G, Wei J, Huang N, Zhang S, Yang F . Matrine derivative YF-18 inhibits lung cancer cell proliferation and migration through down-regulating Skp2. Oncotarget. 2016; 8(7):11729-11738. PMC: 5355299. DOI: 10.18632/oncotarget.14329. View