DFNA5 (ICERE-1) contributes to acquired etoposide resistance in melanoma cells

被引:105
作者
Lage, H
Helmbach, H
Grottke, C
Dietel, M
Schadendorf, D
机构
[1] Humboldt Univ, Inst Pathol, Charite, D-10117 Berlin, Germany
[2] Univ Heidelberg, Skin Canc Unit, DKFZ, D-68135 Mannheim, Germany
[3] Univ Heidelberg, Hosp Mannheim, D-68135 Mannheim, Germany
关键词
drug resistance; malignant melanoma; MeWo; apoptosis;
D O I
10.1016/S0014-5793(01)02304-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Resistance to drug treatment is a common observation in malignant melanoma, In order to analyze alterations in mRNA expression profiles associated with drug resistance in melanoma cells we previously established a panel of various drug-resistant cell variants derived from the human melanoma line MeWo and compared the mRNA expression profiles by a differential display technique, By that approach it could be demonstrated that the expression level of a mRNA encoded by a gene found to be mutated in non-syndromic hearing impairment, DFNA5 (ICERE-1), was distinctly decreased in the 33-fold etoposide-resistant melanoma cell line MeWo ETO I. To evaluate the hypothesis that a decrease in DFNA5 mRNA expression level contributes to the acquired etoposide resistance phenotype exhibited by MeWo ETO 1 cells, this drug-resistant line was stably transfected with the DFNA5-encoding cDNA, Transfected clones showed a 30-35%, reduced etoposide susceptibility by comparing the IC25, IC50 and IC75 values Of these clones with those displayed by the non-transfected, etoposide-resistant melanoma cell line MeWo ETO I and controls. Furthermore, etoposide exposure of stable DFNA5 transfectants resulted in an increase of caspase-3-mediated apoptotic events in DFNA5-transfected clones in comparison to MeWo ETO 1 cells and controls. The data therefore demonstrate that a decrease in DNFA5 mRNA expression level is associated with an increased etoposide resistance in melanoma cells due to an elevated cellular susceptibility to trigger a caspase-3-depending signal pathway leading to programmed cell death. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B,V, All rights reserved.
引用
收藏
页码:54 / 59
页数:6
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