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Title 

Induction of G1 arrest by SB265610 involves cyclin D3 down-regulation and suppression of CDK2 (Thr160) phosphorylation

Authors 

A GodaR L EriksonJong Seog AhnBo Yeon Kim

Publisher 

International Institute of Anticancer Research (IIAR)

Issue Date 

2015

Citation 

Anticancer Research, vol. 35, no. 6, pp. 3235-3243

Keywords 

Cyclin D3G1 arrestp21p38MAPKPhospho(Thr160)-CDK2SB265610

Abstract 

Background/Aim: The current study investigated the mechanisms underlying the antitumor activity of SB265610, a cysteine-amino acid-cysteine (CXC) chemokines receptor 2 (CXCR2) antagonist. Materials and Methods: Cell-cycle progression and regulatory molecules were assessed by flow cytometry, immunoblotting, real-time PCR and immunoprecipitation. Target validation was achieved via RNA interference. Results: G1 arrest induced by SB265610 occurred at concentrations lacking CXCR2 selectivity, persisted upon interleukin 8 (IL8) challenge, and did not affect IL8 downstream target expression. Profiling of G1 regulators revealed cyclin-dependent kinase 2 (CDK2) (Thr160) hypophosphorylation, cyclin D3 gene downregulation, and p21 post-translational induction. However, only cyclin D3 and CDK2 contributed towards G1 arrest. Furthermore, SB265610 induced a sustained phosphorylation of the p38MAPK. Pharmacological interference with p38MAPK significantly abrogated SB265610-induced G1 arrest and normalized the expression of cyclin D3, with restoration of its exclusive binding to CDK6, but with weak recovery of CDK2 (Thr160) hypo-phosphorylation. Conclusion: The present study described the mechanisms for the anti-proliferative activity of SB265610 which may be of value in IL8-rich tumor microenvironments.

ISSN 

0250-7005

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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