Combined inhibition of PAK7, MAP3K7 and CK2alpha kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts.
A panel of kinases whose inhibition increased apoptosis of pancreatic adenocarcinoma cells in vitro was recently established. The aim of this work was to observe in a mouse xenograft model whether inhibition of these kinases would alter pancreatic tumor growth. Rate of apoptosis, caspase-3 activity and cell viability were assessed in two pancreatic cancer cell lines, MiaPaCa2 and BxPC3, after inhibiting selected kinases by transfection of specific siRNAs. For in vivo experiments, MiaPaCa2 cells were injected into the pancreas of nude mice, where they formed tumors. Inhibition of kinases was obtained by repeated intraperitoneal (i.p.) injections of modified O-Methyl (OMe) siRNAs specific for the selected kinases. Tumor volumes were assessed after 21 days. Among selected kinases, PAK7, MAP3K7 and CK2alpha were those whose inhibition increased apoptosis the most in vitro. Simultaneous inhibition of two of them increased apoptosis up to five times. Moreover, inhibiting these kinases had little effect on 10 non-pancreatic cell lines, suggesting pancreatic specificity. In vivo, OMe-siRNAs induced significant but incomplete inhibition of kinase expression (45-75%). Nevertheless, such inhibition resulted in a twofold increase in caspase-3 activity in tumors and a strong reduction in tumor volume (about 75%). In vivo inhibition by OMe-siRNAs of three survival kinases apparently specific for pancreatic cancer cells, PAK7, MAP3K7 and CK2alpha, decreases significantly the growth of xenografted MiaPaCa2 cells. This strategy is therefore of potential clinical interest.
Centre de Recherche INSERM, Unité 624, Stress Cellulaire, Université de la Méditerranée, Case 915 Parc Scientifique de Luminy, Marseille 13288 Cedex 9, France.
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V
Giroux
J L
JL
Iovanna
S
S
Garcia
J-C
JC
Dagorn
D000818:Animals; D017209:Apoptosis; D047390:Casein Kinase II / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000235:genetics* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D047390:Casein Kinase II; D020930:MAP Kinase Kinase Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054462:p21-Activated Kinases; D000099151:MAP Kinase Kinase Kinase 7; C443802:PAK5 protein, human