Apoptosis-mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002. Surgery 2006 Dec;140(6):1009-14; discussion 1014-5
Date
12/26/2006Pubmed ID
17188151DOI
10.1016/j.surg.2006.06.040Scopus ID
2-s2.0-33845626635 (requires institutional sign-in at Scopus site) 70 CitationsAbstract
BACKGROUND: Medullary thyroid cancer (MTC) cells exhibit frequent activation of the PI3K pathway as evidenced by the presence of hyperactivation of Akt kinases and overexpression of neuroendocrine (NE) markers. We hypothesized that the inhibition of the PI3K pathway in MTC may lead to a reduction in cell growth and NE tumor marker production.
METHODS: Human MTC-TT cells were treated with the PI3K inhibitor LY294002 (0-60 micromol/L) for 8 days, and cellular growth was measured. Further, TT cells were treated with nontoxic concentrations of LY294002 for 2 days, and Western blot analyses were performed for phospho-Akt, total Akt, and the NE tumor markers CgA and human achaete-scute homolog1 (ASCL1).
RESULTS: Treatment of TT cells with LY294002 significantly suppressed levels of phospho-Akt. Notably, a dose-dependent reduction in cellular proliferation was also observed. Importantly, NE marker production was also reduced. Mechanistically, we show that cell growth inhibition by PI3K inactivation is mediated by apoptosis attributable to an increase in the levels of cleaved poly(ADP-ribose) polymerase and caspase-3.
CONCLUSIONS: MTC cell growth and NE marker production appear to depend on activation of the PI3K-signaling cascade. Inhibition of this important signal transduction pathway may lead to a possible therapeutic strategy to treat patients with MTC.
Author List
Kunnimalaiyaan M, Ndiaye M, Chen HMESH terms used to index this publication - Major topics in bold
ApoptosisBasic Helix-Loop-Helix Transcription Factors
Carcinoma, Medullary
Caspase 3
Cell Line, Tumor
Cell Proliferation
Chromogranin A
Chromones
Dose-Response Relationship, Drug
Enzyme Inhibitors
Gene Expression Regulation, Neoplastic
Humans
Morpholines
Oncogene Protein v-akt
Phosphatidylinositol 3-Kinases
Phosphorylation
Poly(ADP-ribose) Polymerases
Signal Transduction
Thyroid Neoplasms
