Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival

被引:46
作者
Florenes, VA [1 ]
Skrede, M [1 ]
Jorgensen, K [1 ]
Nesland, JM [1 ]
机构
[1] Norwegian Radium Hosp, Dept Pathol, N-0310 Oslo, Norway
关键词
acetylation; apoptosis; cell cycle; retinoblastoma protein; p53; mitogen-activated protein kinase; trichostatin A;
D O I
10.1097/01.cmr.0000129579.49313.26
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
In the present study the deacetylase inhibitor trichostatin A (TSA) was used to elucidate the effect of protein acetylation on cell cycle progression and survival in seven human malignant melanoma cell lines. It was shown that TSA treatment led to a transient G(2)/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cycl in-dependent kinase inhibitor p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not expressing p21(WAF1/CIP1) constitutively, whereas the levels of both wild-type and mutated p53 protein were reduced. The effect on p53 was not a direct result of inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) activation by TSA, as treatment of the cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) inhibitor PD98059 did not result in decreased p53 protein level. Furthermore, TSA treatment led to reduction in cyclin D1 whereas cyclin D3 accumulated, the latter due to increased protein stability. Similarly, cyclin A protein was reduced whereas cyclin E level was elevated. The effect on p27(Kip1), CDK4 and CDK2 was only marginal. In all the examined cell lines, TSA treatment resulted in a profound induction of apoptosis and cleavage of poly-(ADP-ribose)-polymerase (PARP) indicative of caspase activity. Similarly, TSA-mediated apoptosis was reversed by the caspase-inhibitor z-vad-fmk. Altogether, these results suggest that p21(WAF1/CIP1) in melanomas is silenced by deacetylation, and furthermore that inhibition of deacetylation may have potential in anticancer therapy of melanoma patients. (C) 2004 Lippincott Williams Wilkins.
引用
收藏
页码:173 / 181
页数:9
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