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Paper 22 (1145)
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 role in regulating the growth of carcinoid tumors, have not been characterized. We and others have previously shown 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.
The 26th Annual Meeting of the American
Association of Endocrine Surgeons
April 3rd- 5th,2005 - Paradisus Riviera Cancun.
Muthusamy Kunnimalaiyaan, Ph.D., Sonia Yan, Francis Wong, Yi-Wei Zhang, and Herbert Chen, M.D.
University of Wisconsin, Madison, Wisconsin
Methods: To determine the effect of HES-1 induction on carcinoids, H727 carcinoid tumor cells were stably transduced with a doxycycline-inducible HES-1 construct, creating H727-HES-1 cells. H727-vector control and H727-HES1 cells were then treated with varying concentrations of doxycycline in order to achieve increasing levels of HES-1 protein expression. Cell proliferation was determined using a cell viability assay.
Results: H727-vector and H727-HES-1 cells express minimal HES-1 at baseline. Treatment of H727-HES-1 cells with increasing dosages of doxycycline resulted in dose-dependent increases in HES-1 protein by Western analysis, which was not seen in H727-vector control cells. 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. Therefore, strategies to induce HES-1 expression may be a viable, therapeutic alternative to treat patients with carcinoid and other neuroendocrine tumors.