Pancreatic cancer cell radiation survival and prenyltransferase inhibition: the role of K-Ras.
Activating K-ras mutations are found in approximately 90% of pancreatic carcinomas and may contribute to the poor prognosis of these tumors. Because radiotherapy is frequently used in pancreatic cancer treatment, we assessed the contribution of oncogenic K-ras signaling to pancreatic cancer radiosensitivity. Seven human pancreatic carcinoma lines with activated K-ras and two cell lines with wild-type ras were used to examine clonogenic cell survival after Ras inhibition. Ras inhibition was accomplished by small interfering RNA (siRNA) knockdown of K-ras expression and by blocking Ras processing using a panel of prenyltransferase inhibitors of differing specificity for the two prenyltransferases that modify K-Ras. K-ras knockdown by siRNA or inhibition of prenyltransferase activity resulted in radiation sensitization in vitro and in vivo in tumors with oncogenic K-ras mutations. Inhibition of farnesyltransferase alone was sufficient to radiosensitize most K-ras mutant tumors, although K-Ras prenylation was not blocked. These results show that inhibition of activated K-Ras can promote radiation killing of pancreatic carcinoma in a superadditive manner. The finding that farnesyltransferase inhibition alone radiosensitizes tumors with K-ras mutations implies that a farnesyltransferase inhibitor-sensitive protein other than K-Ras may contribute to survival in the context of mutant K-ras. Farnesyltransferase inhibitors could therefore be of use as sensitizers for pancreatic carcinoma radiotherapy.
Brunner
Thomas B
TB
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6072, USA.
Cengel
Keith A
KA
Hahn
Stephen M
SM
Wu
Junmin
J
Fraker
Douglas L
DL
McKenna
W Gillies
WG
Bernhard
Eric J
EJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000502:physiology
D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D004122:Dimethylallyltranstransferase; D051231:Farnesyltranstransferase