HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells.

Abstract

BACKGROUND:

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions.

RESULTS:

Depletion of HDAC2, but not HDAC1, in the pancreatic cancer cell lines MiaPaCa2 and Panc1 resulted in a marked sensitization towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Correspondingly, the more class I selective HDAC inhibitor (HDACI) valproic acid (VPA) synergized with TRAIL to induce apoptosis of MiaPaCa2 and Panc1 cells. At the molecular level, an increased expression of the TRAIL receptor 1 (DR5), accelerated processing of caspase 8, pronounced cleavage of the BH3-only protein Bid, and increased effector caspase activation was observed in HDAC2-depleted and TRAIL-treated MiaPaCa2 cells.

CONCLUSIONS:

Our data characterize a novel HDAC2 function in PDAC cells and point to a strategy to overcome TRAIL resistance of PDAC cells, a prerequisite to succeed with a TRAIL targeted therapy in clinical settings.

• Authors: Susanne Schüler, Petra Fritsche, Sandra Diersch, Alexander Arlt, Roland M Schmid, Dieter Saur, Günter Schneider
• Journal: Molecular cancer (Mol Cancer) Vol. 9 Pg. 80 (Apr 16 2010) ISSN: 1476-4598 [Electronic] England
• PMID: 20398369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Valproic Acid
• HDAC2 protein, human
• Histone Deacetylase 1
• Histone Deacetylase 2

Topics

• Apoptosis (drug effects, physiology)
• Blotting, Western
• Carcinoma, Pancreatic Ductal (genetics, metabolism)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Gene Expression
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase 1 (genetics, metabolism)
• Histone Deacetylase 2 (genetics, metabolism)
• Humans
• Pancreatic Neoplasms (genetics, metabolism)
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Transfection
• Valproic Acid (pharmacology)