Suppression of U937 human monocytic leukemia cell growth by dideoxypetrosynol A, a polyacetylene from the sponge Petrosia sp., via induction of Cdk inhibitor p16 and down-regulation of pRB phosphorylation.
Dideoxypetrosynol A, a polyacetylene from the marine sponge Petrosia sp., is known to exhibit significant selective cytotoxic activity against a small panel of human tumor cell lines, the mechanisms of which however, are poorly understood. The aim of the present study was to further elucidate the possible mechanisms by which dideoxypetrosynol A exerts its anti-proliferative action in cultured human monocytic leukemia U937 cells. We observed that the proliferation-inhibitory effect of dideoxypetrosynol A was due to the induction of G1 arrest in the cell cycle, the effects of which were associated with up-regulation of cyclin D1 and down-regulation of cyclin E, in a concentration-dependent manner without any change in cyclin-dependent-kinases (Cdks) expression. Dideoxypetrosynol A markedly induced the levels of Cdk inhibitor p16/INK4a expression. Furthermore, down-regulation of phosphorylation of retinoblastoma protein (pRB) by this compound was associated with enhanced binding of pRB and transcription factor E2F-1. Overall, our results demonstrate a combined mechanism involving the inhibition of pRB phosphorylation and induction of p16 as targets for dideoxypetrosynol A, may explain some of its anti-cancer effects.
Park
Cheol
C
Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Korea.
Kim
Gi Young
GY
Kim
Gun Do
GD
Lee
Won Ho
WH
Cheong
Jae Hun
JH
Kim
Nam Deuk
ND
Bae
Song-Ja
SJ
Jung
Jee H
JH
Choi
Yung Hyun
YH
D000114:Acetylene / Q000031:analogs & derivatives / Q000737:chemistry; D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000494:pharmacology; D050684:E2F Transcription Factors / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology*; D010766:Phosphorylation; D011108:Polymers / Q000737:chemistry; D053279:Polyynes; D011161:Porifera; D016160:Retinoblastoma Protein / Q000378:metabolism; D020298:U937 Cells
D000480:Alkynes; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050684:E2F Transcription Factors; D005233:Fatty Alcohols; D011108:Polymers; D016160:Retinoblastoma Protein; C499970:dideoxypetrosynol A; D053279:Polyynes; D000114:Acetylene