Participation of cyclin D1 deregulation in TNP-470-mediated cytostatic effect

Involvement of senescence

Wen Huei Lien, Chi Kuan Chen, Ling Ya Lai, Ya Huey Chen, Ming Ping Wu, Li-Wha Wu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Inhibition of angiogenesis is becoming one promising, alternative approach to stop tumor from growth and spreading to distant organs. TNP-470, an analog of fumagillin, possesses potent anti-angiogenic effects with minimal toxicity in animal tumor models and is now in the phase III of human cancer trial. Although TNP-470 induced endothelial cell cycle arrest at G1 phase via p53 and p21(Cip1), the underlying mechanism of the cytostatic effect of TNP-470 on endothelial cells remains limited. We have found that TNP-470 did not only induce p53 and p21(Cip1) but also cyclin D1 in the basic fibroblast growth factors (bFGF)-treated endothelial cells. The TNP-470-mediated increase of cyclin D1 protein was due to the enhanced expression of mRNA. The induced cyclin D1 formed a complex with cyclin-dependent kinase4 (CDK4) and p21(Cip1). The ability of cyclin D1-associated CDK4 to phosphorylate retinoblastoma (Rb) protein was, however, reduced in the same cells. TNP-470 also significantly increased senescence-associated-β-galactosidase activity (SA-gal), hallmark of cells undergoing senescence. Interestingly, the effect of increased cyclin D1 protein mimicked by overexpression of cyclin D1 increased the sensitivity of human umbilical vein endothelial cells (HUVECs) to TNP-470. In summary, the cytostatic effect of TNP-470 on endothelial cells is in part mediated by induction of senescence and cyclin D1 is a key molecule participating in this event.

Original languageEnglish
Pages (from-to)729-738
Number of pages10
JournalBiochemical Pharmacology
Volume68
Issue number4
DOIs
Publication statusPublished - 2004 Aug 15

Fingerprint

Deregulation
Cyclin D1
Cytostatic Agents
Endothelial cells
Endothelial Cells
Cyclins
Tumors
Galactosidases
Neoplasms
Retinoblastoma Protein
O-(chloroacetylcarbamoyl)fumagillol
Cell Aging
Human Umbilical Vein Endothelial Cells
G1 Phase
Fibroblast Growth Factor 2
Cell Cycle Checkpoints
Toxicity
Animals
Proteins
Animal Models

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Lien, Wen Huei ; Chen, Chi Kuan ; Lai, Ling Ya ; Chen, Ya Huey ; Wu, Ming Ping ; Wu, Li-Wha. / Participation of cyclin D1 deregulation in TNP-470-mediated cytostatic effect : Involvement of senescence. In: Biochemical Pharmacology. 2004 ; Vol. 68, No. 4. pp. 729-738.
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Participation of cyclin D1 deregulation in TNP-470-mediated cytostatic effect : Involvement of senescence. / Lien, Wen Huei; Chen, Chi Kuan; Lai, Ling Ya; Chen, Ya Huey; Wu, Ming Ping; Wu, Li-Wha.

In: Biochemical Pharmacology, Vol. 68, No. 4, 15.08.2004, p. 729-738.

Research output: Contribution to journalArticle

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AU - Lien, Wen Huei

AU - Chen, Chi Kuan

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AU - Wu, Ming Ping

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