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DFNA5 (ICERE‐1) contributes to acquired etoposide resistance in melanoma cells
Author(s) -
Lage Hermann,
Helmbach Heike,
Grottke Claudia,
Dietel Manfred,
Schadendorf Dirk
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02304-3
Subject(s) - melanoma , etoposide , transfection , biology , cell culture , microbiology and biotechnology , apoptosis , cancer research , complementary dna , gene expression , gene , genetics , chemotherapy
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 1. 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 IC 25 , IC 50 and IC 75 values of these clones with those displayed by the non‐transfected, etoposide‐resistant melanoma cell line MeWo ETO 1 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.