Hairy Enhancer of Split-1 (HES-1), a Notch1 effector, inhibits the growth of carcinoid tumor cells.
BACKGROUND
The Notch1-signaling pathway has been shown to regulate the differentiation and growth of carcinoid tumor cells. However, the molecules that mediate Notch1 signaling, as well as their potential roles in regulating the growth of carcinoid tumors, have not been characterized. We and others have shown previously that the transcription factor Hairy Enhancer of Split-1 (HES-1) is upregulated in response to Notch1 signaling, demonstrating that it is a Notch1 effector. We hypothesized that HES-1 may be the essential downstream factor in Notch1-mediated growth regulation of carcinoid tumors.


METHODS
H727 carcinoid tumor cells were transduced stably with a doxycycline-inducible HES-1 construct, creating H727-HES-1 cells. H727-TRE (vector-only control) and H727-HES-1 cells were then treated with varying concentrations of doxycycline to achieve increasing levels of HES-1 protein expression. Cell proliferation was determined with the use of a cell viability assay.


RESULTS
Treatment of H727-HES-1 cells with increasing dosages of doxycycline resulted in dose-dependent increases in HES-1 protein by Western blot analysis. Importantly, induction of HES-1 in carcinoid tumor cells led to suppression of tumor cellular proliferation. Moreover, the degree of carcinoid growth inhibition appeared to be proportional to the level of HES-1 induction.


CONCLUSIONS
HES-1 alone can regulate the growth of carcinoid tumor cells. Furthermore, these results suggest that HES-1 may be the critical downstream effector in the Notch1-signaling pathway.
Kunnimalaiyaan
Muthusamy
M
Department of Surgery, The University of Wisconsin Medical School, University of Wisconsin Comprehensive Cancer Center, Madison, WI, USA.
Yan
Sonia
S
Wong
Francis
F
Zhang
Yi-Wei
YW
Chen
Herbert
H
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000473:pathology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage*; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051881:Receptor, Notch1 / Q000502:physiology; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D004318:Doxycycline; D018398:Homeodomain Proteins; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C065500:ASCL1 protein, human; C078493:HES1 protein, human