Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors.
Malignant insulinoma is a rare form of cancer with a poor prognosis because of metastatic dissemination and untreatable hypoglycemia. Effective chemotherapy of patients who are not cured by surgery is needed. Calcitriol has known anticancer properties on different neoplastic cell lines, but no data are available regarding its activity on tumorigenic pancreatic beta-cells. We analyzed the in vitro effects of calcitriol on the murine insulinoma cell line betaTC(3) and primary cultures of human isolated islets and benign insulinoma. The effect of in vivo calcitriol administration on insulinoma of recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice was also investigated. In betaTC(3), calcitriol induced growth inhibition; apoptosis; down-regulation of insulin gene expression; and nongenomic activation of the MAPK pathway. MAPK kinase inhibitor (UO126) and staurosporine reduced calcitriol-mediated betaTC(3) death, and down-regulation of insulin gene transcription was prevented by staurosporine but not UO126. Calcitriol significantly decreased insulin release and mRNA levels of human islets and insulinoma cells. Finally, recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice treated with calcitriol showed reduced insulinoma volumes because of increased apoptosis of adenomatous cells. Together, these findings provide the rationale for testing the efficacy of calcitriol in the treatment of patients with solid beta-cell tumors.
Galbiati
Francesca
F
Department of Medicine, San Raffaele Scientific Institute, Milan 20132, Italy.
Polastri
Luca
L
Gregori
Silvia
S
Freschi
Massimo
M
Casorati
Mara
M
Cavallaro
Ugo
U
Fiorina
Paolo
P
Bertuzzi
Federico
F
Zerbi
Alessandro
A
Pozza
Guido
G
Adorini
Luciano
L
Folli
Franco
F
Christofori
Gerhard
G
Davalli
Alberto M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002117:Calcitriol / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology*; D007340:Insulinoma / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007328:Insulin; D007329:Insulin Antagonists; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002117:Calcitriol