Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1.

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Krishnan A, Hariharan R, Nair SA, Pillai MR

Fluoxetine mediates G0/G1 arrest by inducing functional inhibition of cyclin dependent kinase subunit (CKS)1.

Biochem Pharmacol. 2008 May 15;75(10):1924-34. doi: 10.1016/j.bcp.2008.02.013. Epub 2008 Feb 17.

PubMed ID

18371935 [ View in PubMed

]

Abstract

Fluoxetine, a well-known antidepressant used clinically for mental depression has gained attention in cancer research owing to its chemosensitizing potential in drug resistant cell lines. Some preliminary reports, however, suggested its independent cytotoxic potential which is not yet well characterized. Our aim in this study was to characterize its antiproliferative activity in tumor cells and to further elucidate the mechanism. We found that fluoxetine sensitized the effect of cyclophosphamide even in drug sensitive MDA MB 231 and SiHa cells. IC(50) values of 28 and 32 microM were obtained for fluoxetine mediated antiproliferative response in these cells. Further, PARP and caspase 3 cleavage analyses confirmed fluoxetine mediated apoptosis at molecular level. Cell cycle analysis showed that fluoxetine arrested cells at G0/G1 phase in a time dependent manner. The application of bioinformatics tools at this juncture predicted CKS1 as one of the possible targets of fluoxetine, which is of relevance to cell cycle biology. Fluoxetine showed the potential to disrupt skp2-CKS1 assembly required for ubiquitination and proteasomal degradation of p27 and p21. Our in vitro results were in agreement with the predictions made in silico. We found that fluoxetine treatment could accumulate p27 and p21, an immediate outcome characteristic of functional inhibition of CKS1. This was accompanied by the accumulation of cyclin E, another possible target of CKS1. We observed CKS1 downregulation also upon prolonged fluoxetine treatment. Fluoxetine had downregulated cyclin A which confirmed G0/G1 arrest at the molecular level. We conclude that fluoxetine induced cell cycle arrest is CKS1 dependent.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Fluoxetine	Cyclin-dependent kinases regulatory subunit 1	Protein	Humans	Unknown	Not Available	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Fluoxetine	Approved Vet Approved	CCNA2	890	downregulated	Fluoxetine results in decreased expression of CCNA2 mRNA	4q27
Fluoxetine	Approved Vet Approved	CKS1B	1163	downregulated	Fluoxetine results in decreased expression of CKS1B mRNA	1q21.3