Differential Na+,K(+)-ATPase activity and cisplatin sensitivity between transformants induced by H-ras and those induced by K-ras.
We examined the differential effects of the H-ras oncogene and the K-ras oncogene on cisplatin sensitivity in murine NIH/3T3 cells transfected with these oncogenes. Although the NIH/3T3 cells transformed with H-ras oncogenes (EJ-NIH/3T3 and Ha8-21) showed an increased resistance to cisplatin compared to the parental NIH/3T3, the cell lines transformed with K-ras oncogenes (DT and 1,8DNP2-2-5) did not. Compared with NIH/3T3, the 2 H-ras transformants reduced both the accumulation of cisplatin and the Na+,K(+)-ATPase activity in the membrane fraction. On the other hand, we observed no significant difference in cellular accumulation of cisplatin or in Na+,K(+)-ATPase activity between parental NIH/3T3 and the K-ras transformants. Since these ras transformants did not affect the cellular metallothionein content, transcriptional level of DNA polymerase beta or activity of glutathione-S-transferase which is not associated with cisplatin sensitivity, these results suggest that cisplatin resistance is brought about by the H-ras oncogene, but not by K-ras, and that induction of cisplatin resistance by H-ras is mainly due to a reduction of cisplatin accumulation and an impairment of Na+,K(+)-ATPase activity in the membrane fraction.
Shinohara
N
N
Department of Urology, Hokkaido University School of Medicine, Sapporo, Japan.
Ogiso
Y
Y
Arai
T
T
Takami
S
S
Nonomura
K
K
Koyanagi
T
T
Kuzumaki
N
N
D016475:3T3 Cells; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000235:genetics; D011905:Genes, ras; D005982:Glutathione Transferase / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D012333:RNA, Messenger; D012334:RNA, Neoplasm; D008668:Metallothionein; D005982:Glutathione Transferase; D004256:DNA Polymerase I; D016283:Proto-Oncogene Proteins p21(ras); D000254:Sodium-Potassium-Exchanging ATPase; D002945:Cisplatin