Search engine for discovering works of Art, research articles, and books related to Art and Culture
ShareThis
Javascript must be enabled to continue!

Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

View through CrossRef
Summary Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish. We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited the expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity.
Title: Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
Description:
Summary Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation.
Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish.
We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer.
In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited the expansion of exocrine pancreas.
In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death.
The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A.
tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218.
These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity.

Related Results

Abstract IA-08: Clinical advances in pancreas adenocarcinoma
Abstract IA-08: Clinical advances in pancreas adenocarcinoma
Abstract Pancreatic adenocarcinoma (PDAC) remains one of the most lethal cancers today and is expected to be the second cause of cancer death in the coming decade. M...
Are Cervical Ribs Indicators of Childhood Cancer? A Narrative Review
Are Cervical Ribs Indicators of Childhood Cancer? A Narrative Review
Abstract A cervical rib (CR), also known as a supernumerary or extra rib, is an additional rib that forms above the first rib, resulting from the overgrowth of the transverse proce...
Emerging Evidence of IgG4-Related Disease in Pericarditis: A Systematic Review
Emerging Evidence of IgG4-Related Disease in Pericarditis: A Systematic Review
Abstract Introduction Immunoglobulin G4-related disease (IgG4-RD) is a recently identified immune-mediated condition that is debilitating and often overlooked. While IgG4-RD has be...
Abstract 1484: Pancreatic cancer and normal pancreas water content and its impact in metabolite quantification
Abstract 1484: Pancreatic cancer and normal pancreas water content and its impact in metabolite quantification
Abstract The absence of early symptoms in pancreatic cancer creates a critical need for identifying new noninvasive biomarkers. Magnetic resonance spectroscopy (MRS)...
Diagnosing pancreatic steatosis in obese patients
Diagnosing pancreatic steatosis in obese patients
Frequency of pancreatic steatosis in adults of general population is up to 35%. Causes of triglyceride accumulation in the pancreas include aging, obesity, type 2 diabetes mellitus...

Back to Top