Suppression of Ki-ras p21 levels leading to growth inhibition of pancreatic cancer cell lines with Ki-ras mutation but not those without Ki-ras mutation.
Ki-ras point mutation characteristically occurs frequently in human pancreatic cancer. To clarify the effect of antisense Ki-ras RNA on various pancreatic cancer cell lines, a plasmid expressing an antisense Ki-ras gene fragment (AS-K-ras-LNSX) was transduced into seven human pancreatic cancer cell lines (AsPC-1, MIA PaCa-2, PANC-1, PSN-1, BxPC-3, Hs 700T, and Hs 766T) by liposome-mediated transfection. Western blot analysis showed that transfection of AS-K-ras-LNSX led to a significant reduction in the amounts of Ki-ras p21 protein in all the pancreatic cancer cell lines except BxPC-3. The growth of pancreatic cancer cell lines having Ki-ras point mutations (AsPC-1, MIA PaCa-2, PANC-1, and PSN-1) was suppressed after transduction of AS-K-ras-LNSX, whereas the effect of the antisense construct on the growth was not significant in cell lines with a wild-type Ki-ras gene (BxPC-3, Hs 700T, and Hs 766T). These results suggest that the pancreatic cancer cells with activated Ki-ras depend heavily on a Ki-ras p21-mediated growth signal pathway for their growth because they were far more susceptible to the suppression of the Ki-ras p21 protein than the cells with wild-type Ki-ras. The remarkably increased dependence of the cancer-cell growth circuitry on one or a few crucial regulatory molecules may thus be a common feature of the cancer cells and implies a novel rationale for the targeting of cancer therapy.
Aoki
K
K
Genetics Division, National Cancer Center Research Institute, Tokyo, Japan.
Yoshida
T
T
Matsumoto
N
N
Ide
H
H
Sugimura
T
T
Terada
M
M
D002455:Cell Division / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012680:Sensitivity and Specificity; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D016372:RNA, Antisense; D015689:Oncogene Protein p21(ras)