Faculty Collaboration Database

Inhibition of the PI3K pathway suppresses hormonal secretion and limits growth in pheochromocytoma cells. World J Surg 2009 Nov;33(11):2452-7

Date

08/12/2009

Pubmed ID

19669229

Pubmed Central ID

PMC3088764

DOI

10.1007/s00268-009-0175-3

Scopus ID

2-s2.0-70350033524 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

BACKGROUND: Operative resection is the only curative treatment for pheochromocytomas. Inhibition of the phosphatidylinositol-3 kinase (PI3K)-Akt pathway has been shown to be an effective treatment of neuroendocrine (NE) tumors in vitro. We hypothesized that inhibition of the PI3K-Akt pathway would be a viable strategy to inhibit growth and hormonal secretion in pheochromocytoma cells.

METHODS: Sixteen pheochromocytomas were analyzed for expression of phosphorylated Akt and the NE marker achaete scute complex-like 1 (ASCL1). Pheochromocytoma PC-12 cells were treated with up to 100 microM of the PI3K-specific inhibitor LY294002 for 48 h. Western blot analysis was used to measure phosphorylated Akt, total Akt, ASCL1, chromogranin A (CgA), and markers of apoptosis. Growth was assessed by a methylthiazolyldiphenyl-tetrazolium (MTT) bromide cellular proliferation assay for six days.

RESULTS: Human pheochromocytomas expressed significant amounts of phosphorylated Akt, and there was a significant correlation between malignant pheochromocytomas and the amount of expressed ASCL1. LY294002 significantly inhibited the PI3K-Akt pathway. Treatment led to a dose-dependent decrease in both ASCL1 and CgA, indicating an alteration in the NE phenotype and hormonal suppression. Treatment decreased cellular proliferation, and cleavage of the apoptotic markers caspase-3 and PARP was observed.

CONCLUSIONS: Human pheochromocytoma tumor samples express high levels of phosphorylated Akt. LY294002 effectively inhibits the PI3K-Akt pathway, suppresses NE tumor markers, and decreases cellular proliferation via apoptosis in vitro. Inhibition of the PI3K pathway may represent a new strategy in the treatment of pheochromocytomas.

Author List

Adler JT, Hottinger DG, Kunnimalaiyaan M, Chen H

MESH terms used to index this publication - Major topics in bold

Adrenal Gland Neoplasms
Cell Proliferation
Chromones
Enzyme Inhibitors
Humans
Morpholines
Pheochromocytoma
Signal Transduction
Tumor Cells, Cultured