Abstract
Sonic Hedgehog (Shh) is abnormally expressed in pancreatic cancer and is associated with disease onset and progression. Inhibition of Shh signaling is thus an attractive clinical target for therapeutic intervention. Most efforts to block Shh signaling have focused on inhibitors of Smoothened, which target the canonical Shh signaling pathway. These approaches have met with limited success, in part due to development of resistance-conferring mutations and contributions from non-canonical signaling pathways. Here, we show that Hedgehog acyltransferase (Hhat), the enzyme responsible for the attachment of palmitate onto Shh, is a novel target for inhibition of Shh signaling in pancreatic cancer cells. Depletion of Hhat with lentivirally delivered small hairpin RNA decreased both anchorage-dependent and independent proliferation of human pancreatic cancer cells. In vivo, Hhat knockdown led to reduction of tumor growth in a mouse xenograft model of pancreatic cancer. RU-SKI 43, a small molecule inhibitor of Hhat recently developed by our group, reduced pancreatic cancer cell proliferation and Gli-1 activation through Smoothened-independent non-canonical signaling. In addition, RU-SKI 43 treatment inhibited two key proliferative pathways regulated by Akt and mTOR. This work demonstrates that Hhat has a critical role in pancreatic cancer and that a small molecule inhibitor of Hhat can successfully block pancreatic cancer cell proliferation. It also highlights the importance of developing optimized Hhat inhibitors to be used as therapeutics in pancreatic cancer, as well as in other malignancies characterized by Shh overexpression.
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Acknowledgements
We thank Raisa Louft-Nisenbaum for technical assistance, Dr Elisa de Stanchina for performing tumor xenograft studies, Dr Nian Wu for pharmacokinetic analyses, the MSKCC Genomics and Molecular Cytology Cores, and Jessica Rios-Esteves and Rayshonda Hardy for reading the manuscript. This work was supported by NIH grants GM57966 and CA158474, by MSKCC Cycle for Survival, by the Geoffrey Beene Cancer Research Foundation, by Mr William H Goodwin and Mrs Alice Goodwin and by the Commonwealth Foundation for Cancer Research and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center.
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Petrova, E., Matevossian, A. & Resh, M. Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma. Oncogene 34, 263–268 (2015). https://doi.org/10.1038/onc.2013.575
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DOI: https://doi.org/10.1038/onc.2013.575
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