Mécanismes moléculaires du signal pro-apoptotique du récepteur de somatostatine sst2

Molecular mechanisms of sst2 somatostatin receptor apoptotic signal

• Auteur / Autrice : Julie Guillermet-Guibert
• Direction : Christiane Susini
• Type : Thèse de doctorat
• Discipline(s) : Innovation pharmacologique
• Date : Soutenance en 2005
• Etablissement(s) : Toulouse 3

Mots clés

Mots clés contrôlés

Cancer

Pancréas

Récepteurs

Somatostatine

Complexes récepteur-ligand

Apoptose

Mots clés libres

Apoptose

Ligand de mort

Somatostatine

Cancer du pancréas

Résistance

Rcpg

NF-kappaBP

PI3k

Résumé

I first uncovered a previously unappreciated action, and the signalling pathways associated, induced by the GPCR somatostatin receptor 2 (sst2) leading or sensitizing to apoptosis. I studied the involvement of apoptosis pathways, especially of BCL-2 protein and of NF-kB and JNK pathways in BxPC-3 and in NIH3T3 models. Remarkably, 90% of human pancreatic adenocarcinomas show a loss of sst2 expression. We documented that loss of sst2 expression in pancreatic cancer confers a growth advantage, since sst2 re-expression in a pancreatic cancer model devoid of sst2 receptor induces apoptosis, sensitizes these cells to apoptosis induced by death ligand and gemcitabine (reference treatment for pancreatic cancer), which argues for sst2 gene transfer therapy in pancreatic cancer. Besides, sst2 in-activates PI3K, via a direct interaction between sst2 and p85, resulting in apoptosis and anti-tumorigenic effect. That the binding of PI3K results in its inhibition has not been previously described.