TY - JOUR
T1 - Participation of cyclin D1 deregulation in TNP-470-mediated cytostatic effect
T2 - Involvement of senescence
AU - Lien, Wen Huei
AU - Chen, Chi Kuan
AU - Lai, Ling Ya
AU - Chen, Ya Huey
AU - Wu, Ming Ping
AU - Wu, Li Wha
N1 - Funding Information:
First, we would like to express our great gratitude to Dr. Ming-Der Lai for his helpful discussion while preparing the manuscript. Second, we would like thank to Takeda Pharmaceuticals for TNP-470. This work was mainly supported by a 3-year Career Development Grant (NHRI-EX9016BC) from National Health Research Institute in Taiwan and in part by the MOE program promoting academic excellence of University under the grant number 91-B-FA09-2-4.
PY - 2004/8/15
Y1 - 2004/8/15
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bcp.2004.05.020
DO - 10.1016/j.bcp.2004.05.020
M3 - Article
C2 - 15276080
AN - SCOPUS:3242663393
SN - 0006-2952
VL - 68
SP - 729
EP - 738
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -
