Inhibition of phosphatidylinositol 3-kinase/Akt signaling suppresses tumor cell proliferation and neuroendocrine marker expression in GI carcinoid tumors.
BACKGROUND
Overactivation of PI3K/Akt signaling facilitates tumor proliferation in several cancers. We have shown that various signal transduction pathways promote tumorigenesis in carcinoid tumors, which exhibit endogenously high levels of active, phosphorylated Akt. Therefore, we hypothesized that inhibition of the PI3K/Akt pathway would suppress carcinoid tumor cell growth and neuroendocrine (NE) marker production.


METHODS
Human carcinoid BON cells were treated in vitro with LY294002, a PI3-kinase inhibitor, or transfected with Akt1 siRNA. Tumor cell proliferation was measured by MTT for 6 days. The effect of LY294002 or Akt1 siRNA treatment was assessed by Western analysis. We examined the levels of phosphorylated Akt, total Akt, Akt1, and the NE markers human achaete-scute homolog1 (ASCL1) and chromogranin A (CgA).


RESULTS
Treatment of BON cells with LY294002 reduced tumor cell proliferation (76%) in a dose-dependent manner. Growth also decreased in Akt1 siRNA transfected cells (26%). Levels of active, phosphorylated Akt and the NE tumor markers, ASCL1 and CgA, were diminished with both LY294002 and Akt1 siRNA treatments proportional to the degree of Akt inhibition. Total Akt, Akt2, and Akt3 levels were unaffected by these experiments.


CONCLUSIONS
These data indicate that PI3K/Akt signaling performs a critical role in human carcinoid tumor cell survival and NE hormone generation. Furthermore, the development of novel therapeutics targeting Akt1 or components of the PI3K/Akt pathway may enhance the management of carcinoid disease.
Pitt
Susan C
SC
Endocrine Surgery Research Laboratory, Department of Surgery, University of Wisconsin, Madison, WI, USA.
Chen
Herbert
H
Kunnimalaiyaan
Muthusamy
M
D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002276:Carcinoid Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D053379:Chromogranin A / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology*; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D018358:Neuroendocrine Tumors / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D053379:Chromogranin A; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one