K-Ras Promotes Tumorigenicity through Suppression of Non-canonical Wnt Signaling

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/Ca2+ 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-RasV12-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. [Display omitted] •Oncogenic K-Ras and H-Ras differ in tumor initiation via non-canonical Wnt signaling•Suppression of Fzd8-mediated Wnt/Ca2+ signaling is essential to K-Ras malignancy•K-Ras-CaM interaction modulates the Wnt/Ca2+ signaling pathway•Prostratin compromises the K-Ras-CaM interaction and so prevents tumorigenicity The interaction between K-Ras and calmodulin (CaM) modulates tumor formation through inhibition of CaM kinase activity and suppression of Fzd8-mediated Wnt/Ca2+ signaling. This interaction does not occur with H-Ras or N-Ras, and disruption of the K-Ras-CaM interaction by the orally active natural product prostratin represses tumor growth.