Poster Sessions

CANCER-14

Tura Camilli

T.C Camilli, B. Chien, M. Xu, M.O. O\'Connell, B. Frank, F. Indig, D. Taub, A. Weeraratna

Klotho: A Common Thread between Aging and Cancer?

Cancer mortality rates increase with age, suggesting a link between these fates. Cellular ageing in the form of increased senescence in the surrounding microenvironment is thought to contribute to increased metastasis, but the molecular mechanisms involved are unclear. We have shown that Wnt5A-mediated signaling, can promote melanoma metastasis. Wnt signaling can be modified by the protein Klotho, which has been implicated in the regulation of ageing. The loss of Klotho leads to premature aging in mice. We investigated the reciprocal regulatory mechanism between Klotho and Wnt5A. Klotho and Wnt5a expression are inversely correlated both at the gene and protein level, such that highly metastatic cells which express high levels of Wnt5A express low levels of Klotho, and vice versa. Treatment with recombinant Wnt5A decreases Klotho expression and increases motility in non-metastatic melanoma cells. Conversely, treatment of highly metastatic cells with recombinant Klotho inhibits their motility. Wnt5A effects on motility are partially due to activation of calpain-mediated filamin cleavage. Since calpain activation is inhibited in the presence of Klotho, we investigated whether Klotho could perpetrate its inhibitory effects on Wnt5A-mediated motility via the regulation of Wnt5a-activated calpain cleavage of filamin. Indeed, Klotho treatment affected filamin reorganization, suggesting that a complex loop between Klotho, Wnt5A and Filamin exists, and affects cell invasion. These data suggest that the loss of Klotho may contribute to melanoma progression, perhaps providing a common link between cancer and ageing.