title: K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling.
abstract: K-Ras and H-Ras share identical effectors and have similar properties; however, the high degree of tumor-type specificity associated with K-Ras and H-Ras mutations suggests that they have unique roles in oncogenesis. Here, we report that oncogenic K-Ras, but not H-Ras, suppresses non-canonical Wnt/Ca(2+) signaling, an effect that contributes strongly to its tumorigenic properties. K-Ras does this by binding to calmodulin and so reducing CaMKii activity and expression of Fzd8. Restoring Fzd8 in K-Ras mutant pancreatic cells suppresses malignancy, whereas depletion of Fzd8 in H-Ras(V12)-transformed cells enhances their tumor initiating capacity. Interrupting K-Ras-calmodulin binding using genetic means or by treatment with an orally active protein kinase C (PKC)-activator, prostratin, represses tumorigenesis in K-Ras mutant pancreatic cancer cells. These findings provide an alternative way to selectively target this "undruggable" protein.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
authors.forename: Man-Tzu
authors.initials: MT
authors.lastname: Wang
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Holderfield
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Galeas
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
authors.forename: Reyno
authors.initials: R
authors.lastname: Delrosario
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
authors.forename: Minh D
authors.initials: MD
authors.lastname: To
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1450 3(rd) Street, San Francisco, CA 94158, USA. Electronic address: mccormic@cc.ucsf.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002147:Calmodulin / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010212:Papilloma / Q000378:metabolism; D010703:Phorbol Esters / Q000008:administration & dosage; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D002147:Calmodulin; C529739:Fzd8 protein, human; C117307:KRAS protein, human; D010703:Phorbol Esters; D011956:Receptors, Cell Surface; C070999:prostratin; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)