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Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma
E Petrova1, A Matevossian2, M D Resh3
11] 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.
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.
Insights
Hedgehog acyltransferase (Hhat) is a new target for pancreatic cancer therapy. Inhibiting Hhat blocks cancer cell growth and tumor progression by disrupting Sonic Hedgehog (Shh) signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sonic Hedgehog (Shh) signaling is dysregulated in pancreatic cancer, driving disease progression.
- Targeting canonical Shh pathways via Smoothened inhibitors has shown limited efficacy due to resistance and non-canonical signaling.
- Hedgehog acyltransferase (Hhat) is crucial for Shh protein modification and signaling activation.
Purpose of the Study:
- To investigate Hhat as a novel therapeutic target in pancreatic cancer.
- To evaluate the efficacy of Hhat inhibition in blocking pancreatic cancer cell proliferation and tumor growth.
- To explore the mechanism of Hhat inhibition on Shh signaling and downstream pathways.
Main Methods:
- Depletion of Hhat using lentivirally delivered small hairpin RNA (shRNA) in human pancreatic cancer cells.
- Assessment of cell proliferation (anchorage-dependent and -independent) in vitro.
- Evaluation of tumor growth in a mouse xenograft model following Hhat knockdown.
- Treatment with RU-SKI 43, a small molecule Hhat inhibitor, and analysis of its effects on cell proliferation, Gli-1 activation, and key signaling pathways (Akt, mTOR).
Main Results:
- Hhat depletion significantly reduced pancreatic cancer cell proliferation in vitro.
- Hhat knockdown led to decreased tumor growth in a preclinical mouse model.
- The Hhat inhibitor RU-SKI 43 suppressed pancreatic cancer cell proliferation and Gli-1 activation via Smoothened-independent pathways.
- RU-SKI 43 treatment also inhibited the Akt and mTOR proliferative pathways.
Conclusions:
- Hhat is a critical mediator of pancreatic cancer progression and a viable therapeutic target.
- Inhibition of Hhat, particularly with small molecule inhibitors like RU-SKI 43, effectively blocks pancreatic cancer cell proliferation and tumor growth.
- Targeting Hhat offers a promising strategy for pancreatic cancer treatment, potentially overcoming resistance associated with Smoothened inhibitors and impacting non-canonical signaling.
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