Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma.
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.
1] Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Graduate Program in Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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Petrova
1] Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, New York, NY, USA.
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Matevossian
1] Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Gerstner Sloan-Kettering Graduate School of Biomedical Sciences, New York, NY, USA [3] Graduate Programs in Cell Biology and Biochemistry, Weill Graduate School of Medical Sciences of Cornell University, New York, NY, USA.
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D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D000217:Acyltransferases; C105599:HHAT protein, human