Sonic Hedgehog promotes tumor cell survival by inhibiting CDON pro-apoptotic activity.
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 autocrine or paracrine manner, actually provides a selective tumor growth advantage by blocking CDON-induced apoptosis. In support of this notion, we present the preclinical demonstration that interference with the SHH-CDON interaction triggers a CDON-dependent apoptosis in vitro and tumor growth inhibition in vivo. The latter observation qualifies CDON as a relevant alternative target for anticancer therapy in SHH-expressing tumors.
Apoptosis, Cancer and Development Laboratory-Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Cancérologie de Lyon, Institut National de la Santé et de la Recherche Médicale (INSERM) U1052- Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR5286), Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
Céline
C
Delloye-Bourgeois
Benjamin
B
Gibert
Nicolas
N
Rama
Jean-Guy
JG
Delcros
Nicolas
N
Gadot
Jean-Yves
JY
Scoazec
Robert
R
Krauss
Agnès
A
Bernet
Patrick
P
Mehlen
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C107286:CDON protein, human; D015815:Cell Adhesion Molecules; D053823:Hedgehog Proteins; D025521:Tumor Suppressor Proteins