Secretin receptor promotes the proliferation of endocrine tumor cells via the PI3K/AKT pathway.
The secretin receptor (SR), a G protein-coupled receptor, mediates the effects of the gastrointestinal hormone secretin on digestion and water homeostasis. Recently, high SR expression has been observed in pancreatic ductal adenocarcinomas, cholangiocellular carcinomas, gastrinomas, and bronchopulmonary carcinoid tumors. Receptor overexpression associates with enhanced secretin-mediated signaling, but whether this molecule plays an independent role in tumorigenesis is currently unknown. We recently discovered that pheochromocytomas developing in rats affected by the MENX (multiple endocrine neoplasia-like) syndrome express at very high-level Sctr, encoding SR. We here report that SR are also highly abundant on the membranes of rat adrenal and extraadrenal pheochromocytoma, starting from early stages of tumor development, and are functional. PC12 cells, the best characterized in vitro pheochromocytoma model, also express Sctr at high level. Thus, we used them as model to study the role of SR in neoplastic transformation. Small interfering RNA-mediated knockdown of Sctr decreases PC12 cells proliferation and increases p27 levels. The proproliferative effect of SR in PC12 cells is mediated, in part, by the phosphatidylinositol 3 kinase (PI3K)/serine-threonine protein kinase (AKT) pathway. Transfection of Sctr in Y1 adrenocortical carcinoma cells, expressing low endogenous levels of Sctr, stimulates cell proliferation also, in part, via the PI3K/AKT signaling cascade. Because of the link between SR and PI3K/AKT signaling, tumor cells expressing high levels of the receptor (MENX-associated primary pheochromocytoma and NCI-H727 human bronchopulmonary carcinoid cells) respond well and in a SR-dependent manner to PI3K inhibitors, such as NVP-BEZ235. The association between SR levels and response to PI3K inhibition might open new avenues for the treatment of tumors overexpressing this receptor.
Institute of Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Misu
M
Lee
Beatrice
B
Waser
Jean-Claude
JC
Reubi
Natalia S
NS
Pellegata
D000310:Adrenal Gland Neoplasms / Q000378:metabolism* / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012633:Secretin / Q000494:pharmacology / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic
D000631:Aminopyridines; D005765:Gastrointestinal Agents; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D012633:Secretin; C571178:NVP-BKM120; C029937:secretin receptor; C531198:dactolisib