Carcinoid tumor cell growth suppression by PI3 Kinase-Akt pathway inhibition

Abstract

Introduction: The PI3 Kinase-Akt signaling pathway is known to promote tumor cell survival by suppressing pro-apoptotic proteins. We have previously shown that human carcinoid tumor cells utilize several signal transduction pathways to modulate cellular growth and neuroendocrine (NE) marker production. Furthermore, human carcinoid cells have endogenously high levels of active, phosphorylated Akt. Therefore, we hypothesized that the inhibition of the PI3 Kinase-Akt pathway may lead to a reduction of carcinoid tumor cell growth and NE marker production. Methods: Human gastrointestinal (GI) carcinoid BON cells were treated with varying concentrations of the PI3 kinase inhibitor LY294002 (0-100 μM) for a two-day time period. Western analyses were performed for active, phospho-Akt, total Akt, and the NE marker human achaete-scute homolog1 (hASH1). Cellular growth was measured both by MTT assay and cell counts for 8 days. Results: Treatment of BON cells with LY294002 led to a dose-dependent reduction in the levels of the active, phosphorylated Akt, illustrating the successful inhibition of the PI3 Kinase-Akt pathway. Moreover, LY294002 significantly suppressed carcinoid tumor cell growth and production of hASH1. Importantly, these reductions in cellular growth and NE marker production were directly proportional to the degree of Akt inhibition. Conclusion: Human carcinoid tumor cell growth and hASH1 production appears to be dependent upon activation of the PI3 Kinase-Akt signaling pathway. Therefore, inhibition of this important signal transduction pathway could be a potential therapeutic strategy to treat and palliate patients with carcinoid tumors.