Apoptosis-mediated medullary thyroid cancer growth suppression by the PI3K inhibitor LY294002.
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.
Kunnimalaiyaan
Muthusamy
M
Department of Surgery, Section of Endocrine Surgery, Endocrine Surgery Research Laboratories, The University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA.
Ndiaye
Mary
M
Chen
Herbert
H
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053379:Chromogranin A / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*
D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D053379:Chromogranin A; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C065500:ASCL1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one