Tautomycin suppresses growth and neuroendocrine hormone markers in carcinoid cells through activation of the Raf-1 pathway.
BACKGROUND
Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Raf-1 pathway activation has been shown to suppress hormone production in carcinoid cells. We investigated a novel treatment for carcinoid cell growth based on pharmacologic Raf-1 activation using the compound tautomycin (TTY).


METHODS
Human carcinoid cells were treated with TTY for 48 hours. Western blot analysis was used to demonstrate Raf-1 pathway activation by phosphorylation of ERK1/2 and to determine the effect on NE tumor markers. Cellular growth was measured by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay.


RESULTS
Treatment with TTY resulted in dose-dependent activation of the Raf-1 pathway. Furthermore, a significant decrease in NE tumor markers was seen. Importantly, TTY inhibited carcinoid cellular growth and induced the cell-cycle inhibitors p21 and p27.


CONCLUSIONS
TTY activates the Raf-1 pathway, limits carcinoid cell growth, and suppresses NE marker production in vitro. This new compound warrants further investigation in animal models of carcinoid cancer.
Pinchot
Scott N
SN
Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin, Madison, WI, USA.
Adler
Joel T
JT
Luo
Yinggang
Y
Ju
Jianhua
J
Li
Wenli
W
Shen
Ben
B
Kunnimalaiyaan
Muthusamy
M
Chen
Herbert
H
D014408:Biomarkers, Tumor / Q000378:metabolism; D002276:Carcinoid Tumor; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009490:Neurosecretory Systems / Q000187:drug effects*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013141:Spiro Compounds / Q000494:pharmacology*
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D011714:Pyrans; D013141:Spiro Compounds; C053079:tautomycin; D019908:Proto-Oncogene Proteins c-raf