Pancreatic Neuroendocrine Tumors Are Characterized by Loss of <i>Noxa</i> Expression that Can be Recovered by the Proteasome Inhibitor Bortezomib

Abstract

Prognosis in well-differentiated neuroendocrine carcinomas varies considerably and therapeutic targets for metastatic disease are urgently needed. cDNA microarray studies in our laboratory revealed a significantly lower expression level of the Noxa -gene in human pancreatic neuroendocrine neoplasms (PNENs) as compared to normal islet cells. To determine the validity of the downregulation of Noxa in PNENs, benign and malignant tumors from both sporadic and MEN1 patients were selected for expression analysis. To further verify the findings, neuroendocrine BON1 and QGP cell lines were tested for Noxa expression and its recovery by treatment with the proteasome inhibitor bortezomib. The expression of Noxa was significantly downregulated in 20 PNENs (p = 0.0036). There was no significant difference between MEN1 and sporadic tumors. However, the malignant tumors showed a more significant decrease as compared to benign tumors (p = 0.0385) and the decrease in expression in tumors greater than 20 mm was very highly significant (p < 0.0001). Neither the BON1 nor QGP1 cell lines displayed expression of Noxa protein in the absence of the proteasome inhibitor, Bortezomib. After stimulation with the drug for 16 h, the expression was induced in both cell lines that are correlated with an increase in the level of c-MYC expression, cleaved caspase 3 and cell death. The low expression level of Noxa in PNENs contributes to the inability of these tumor entities to undergo apoptosis. The recovery of Noxa expression following treatment with the proteasome inhibitor, bortezomib, leading to caspase activation and cell death supports the use of such drugs for the treatment of these tumor entities.