Winning Abstracts from the 2009 Medical Student Abstract Competition: Combined Targeting of Histone Deacetylases and Hedgehog Signaling Cooperatively Induces Cell Death and Suppresses Proliferation In Pancreatic Cancer
Authors: First Author: Stephen G. Chun, University of Hawaii, Second Author: Weiqiang Zhou, Third Author: Nelson S. Yee
Pancreatic adenocarcinoma is almost uniformly fatal and the combination of agents that target distinct cellular signaling mechanisms may improve the efficacy of therapy. Histone deacetylases (HDACs) control cellular functions through epigenetic modulation, and inhibitors of HDACs suppress cell growth in pancreatic adenocarcinoma. The hedgehog (HH) pathway regulates the development of the pancreas, and aberrantly activated HH signaling promotes the initiation and progression of pancreatic neoplasia. Based upon these lines of evidence, we hypothesize that HDACs and the HH pathway cooperatively interact to regulate cellular proliferation of the exocrine pancreas.
A combination of an HDACs inhibitor (HDACi) and HH pathway inhibitor (HHi) was evaluated for their ability to suppress the growth of the gemcitabine-resistant pancreatic adenocarcinoma cell lines as well as their underlying molecular mechanisms.
Using soft agar colony assay, we showed that the combination of HDACi and HHi supra-additively suppressed cellular proliferation. Flow cytometric analyses indicated a cooperative induction of cell death and accumulation of cells in G0/G1 phases of the cell cycle. Immunohistochemistry revealed ductal epithelial differentiation and altered localization of survivin. Examination of the molecular mechanisms by immunoblotting and real-time polymerase chain reaction demonstrated repression of HH signaling, stimulation of bax expression, up-regulation of the cyclin-dependent kinase inhibitors p21 and p27, and down-regulation of cyclin D1. There was a supra-additive induction of caspases 3 and 7, although the pan-caspase inhibitor z-VAD-FMK failed to abolish the anti-proliferative effects of HDACi and HHi, suggesting that caspase-independent mechanisms are involved.
This translational study elucidates a novel interaction between HDACs and HH pathway that cooperatively regulates pancreatic cancer proliferation and may be required for pancreatic cancer stem cell homeostasis. Based upon this interaction, we have developed a molecular target-based strategy that overcomes chemo-resistance in pancreatic cancer cells by chemically inhibiting HH signaling and HDACs. Ongoing translational in vivo studies will evaluate the therapeutic potential of combining HDACs and HH inhibitors for pancreatic adenocarcinoma.
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