Activating transcription factor 4 increases the cisplatin resistance of human cancer cell lines.
Resistance to cisplatin is a major problem in the treatment of solid tumors. To investigate the determinants of cisplatin resistance, we have identified cisplatin-inducible genes by differential display of mRNA. One of the cisplatin-inducible genes was identified as activating transcription factor 4 (ATF4). Northern blot analysis demonstrated that expression of ATF4 is inducible at the transcriptional level. Its expression is also up-regulated in two cisplatin-resistant cell lines. We tested whether cellular levels of ATF4 are responsible for cisplatin sensitivity by examining 11 human lung cancer cell lines. Expression of ATF4 was found to correlate with cisplatin sensitivity (P = 0.01). We also evaluated the cisplatin sensitivity of two stable transfectants overexpressing ATF4. Both were less sensitive to cisplatin than the parental cells but equally sensitive to vincristine. Our findings suggest that levels of ATF4 expression could help to predict cisplatin sensitivity.
Tanabe
Mizuho
M
Departments of Molecular Biology and. Surgery II, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Fukuoka, Japan.
Izumi
Hiroto
H
Ise
Tomoko
T
Higuchi
Shun
S
Yamori
Takao
T
Yasumoto
Kosei
K
Kohno
Kimitoshi
K
D051701:Activating Transcription Factor 4; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; D002945:Cisplatin