Induction of G1 Arrest by SB265610 Involves Cyclin D3 Down-regulation and Suppression of CDK2 (Thr160) Phosphorylation.

Autor:	Goda AE; World Class Institute, Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt., Erikson RL; World Class Institute, Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, U.S.A., Ahn JS; Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea., Kim BY; World Class Institute, Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Republic of Korea bykim@kribb.re.kr.
Jazyk:	angličtina
Zdroj:	Anticancer research [Anticancer Res] 2015 Jun; Vol. 35 (6), pp. 3235-43.
Abstrakt:	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 down-regulation, 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. (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
Databáze:	MEDLINE
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