Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity

PLoS Biology
Céline Delloye-BourgeoisPatrick Mehlen

Abstract

The Hedgehog signaling is a determinant pathway for tumor progression. However, while inhibition of the Hedgehog canonical pathway-Patched-Smoothened-Gli-has proved efficient in human tumors with activating mutations in this pathway, recent clinical data have failed to show any benefit in other cancers, even though Sonic Hedgehog (SHH) expression is detected in these cancers. Cell-adhesion molecule-related/down-regulated by Oncogenes (CDON), a positive regulator of skeletal muscle development, was recently identified as a receptor for SHH. We show here that CDON behaves as a SHH dependence receptor: it actively triggers apoptosis in the absence of SHH. The pro-apoptotic activity of unbound CDON requires a proteolytic cleavage in its intracellular domain, allowing the recruitment and activation of caspase-9. We show that by inducing apoptosis in settings of SHH limitation, CDON expression constrains tumor progression, and as such, decreased CDON expression observed in a large fraction of human colorectal cancer is associated in mice with intestinal tumor progression. Reciprocally, we propose that the SHH expression, detected in human cancers and previously considered as a mechanism for activation of the canonical pathway in an a...Continue Reading

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Citations

Aug 2, 2014·Nature Cell Biology·Lorenzo GalluzziGuido Kroemer
Oct 15, 2014·Journal of the National Cancer Institute·Benjamin GibertPatrick Mehlen
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Methods Mentioned

BETA
transfection
PCR
immunoprecipitation
dot blot
laser capture microdissection
ELISA
cleavage assay
xenografts
biopsies
Assay

Software Mentioned

AxioVision
Quantity one

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