Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility.
We have previously shown that Wnt5A-mediated signaling can promote melanoma metastasis. It has been shown that Wnt signaling is antagonized by the protein Klotho, which has been implicated in aging. We show here that in melanoma cells, expressions of Wnt5A and Klotho are inversely correlated. In the presence of recombinant Klotho (rKlotho), we show that Wnt5A internalization and signaling is decreased in high Wnt5A-expressing cells. Moreover, in the presence of rKlotho, we observe an increase in Wnt5A remaining in the medium, coincident with an increase in sialidase activity, and decrease in syndecan expression. These effects can be inhibited using a sialidase inhibitor. In addition to its effects on Wnt5A internalization, we also demonstrate that Klotho decreases melanoma cell invasive potential by a second mechanism that involves the inhibition of calpain and a resultant decrease in filamin cleavage, which we demonstrate is critical for melanoma cell motility.
Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Tura C
TC
Camilli
Mai
M
Xu
Michael P
MP
O'Connell
Bonnie
B
Chien
Brittany P
BP
Frank
Sarah
S
Subaran
Fred E
FE
Indig
Patrice J
PJ
Morin
Stephen M
SM
Hewitt
Ashani T
AT
Weeraratna
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003285:Contractile Proteins / Q000378:metabolism*; D018450:Disease Progression; D064448:Filamins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
D003285:Contractile Proteins; D064448:Filamins; D019812:Heparan Sulfate Proteoglycans; D008840:Microfilament Proteins; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins