Regulation of the resistance to TRAIL-induced apoptosis as a new strategy for pancreatic cancer.

Abstract

BACKGROUND:

Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in a wide variety of tumor cells, but it does not cause toxicity in the majority of normal cells. Therefore, TRAIL could become a suitable agent for anticancer therapies. However, a number of tumor cell lines are known to be resistant to TRAIL-induced apoptosis. The purpose of this study was to determine the mechanisms of resistance to TRAIL in pancreatic cancer cells.

METHODS:

In human pancreatic cancer cell lines, the sensitivity to TRAIL-induced apoptosis was tested. The expression of TRAIL receptors (DR4, DR5, DcR1, and DcR2) and the expression of death signal-transducing proteins were investigated. In the TRAIL-resistant pancreatic cancer cells, effects of cycloheximide, a protein synthesis inhibitor, on death signal-transducing proteins were tested. Finally, the effects of the combined treatment with cycloheximide and TRAIL on the induction of apoptosis and on the expression of death signal-transducing proteins were examined.

RESULTS:

Pancreatic cancer cells responded to TRAIL in a different way. Resistant cell lines, AsPC-1, Suit-2, and CFPAC-1, expressed higher levels of FLIP-S protein, one of the splice variants of FLIP. Cycloheximide reduced the expression of FLIP in the resistant cells. Combined treatment with cycloheximide and TRAIL induced cleaved forms of caspases and simultaneously restored the sensitivity to TRAIL-induced apoptosis in the resistant cells.

CONCLUSIONS:

Pancreatic cancer cells are resistant to TRAIL-induced apoptosis via strong expression of the anti-apoptotic protein FLIP-S. Suppression of FLIP-S by cycloheximide restored sensitivity to TRAIL-induced apoptosis in resistant cancer cells. These findings may provide useful information for the development of TRAIL-based therapeutic strategies aimed at restoring the functionality of apoptotic pathways in pancreatic cancer cells.

• Authors: Tomohiko Mori, Ryuichiro Doi, Eiji Toyoda, Masayuki Koizumi, Daisuke Ito, Kazuhiro Kami, Atsushi Kida, Toshihiko Masui, Yoshiya Kawaguchi, Koji Fujimoto
• Journal: Surgery (Surgery) Vol. 138 Issue 1 Pg. 71-7 (Jul 2005) ISSN: 0039-6060 [Print] United States
• PMID: 16003319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Membrane Glycoproteins
• Protein Synthesis Inhibitors
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• TNFRSF10B protein, human
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Cycloheximide
• Caspases

Topics

• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• Caspases (metabolism)
• Cell Line, Tumor
• Cycloheximide (pharmacology)
• Drug Resistance, Neoplasm
• Gene Expression (drug effects)
• Humans
• Membrane Glycoproteins (pharmacology)
• Pancreatic Neoplasms (drug therapy, pathology)
• Protein Synthesis Inhibitors (pharmacology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor (genetics)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha (pharmacology)