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 μM 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.
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Acknowledgments
Joel T. Adler is a Howard Hughes Medical Institute Research Training Fellow and is supported by the University of Wisconsin General Clinical Research Center. Additional support was provided by National Institutes of Health grants R21-CA117117, R01-CA121115, and R01-CA109053; the George H. A. Clowes, Jr., Memorial Research Career Development Award of the American College of Surgeons; a Carcinoid Cancer Foundation research award (to H.C.), and a Carcinoid Cancer Foundation Research Award (to M.K.).
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Adler, J.T., Hottinger, D.G., Kunnimalaiyaan, M. et al. Inhibition of the PI3K Pathway Suppresses Hormonal Secretion and Limits Growth in Pheochromocytoma Cells. World J Surg 33, 2452–2457 (2009). https://doi.org/10.1007/s00268-009-0175-3
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DOI: https://doi.org/10.1007/s00268-009-0175-3