Calmodulin inhibition contributes to sensitize TRAIL-induced apoptosis in human lung cancer H1299 cells.

Abstract

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells. However, TRAIL alone is not effective in treating TRAIL-resistant tumors. We evaluated the effect of 180 enzyme inhibitors on TRAIL-induced apoptosis in human lung cancer H1299 cells, and found fluphenazine-N-2-chloroethane (a calmodulin (CaM) antagonist) sensitized TRAIL-induced apoptosis. Interestingly, in the presence of TRAIL, it increased caspase-8 binding to the Fas-associated death domain (FADD), but decreased binding of FADD-like interleukin-1beta-converting enzyme inhibitory proteins (FLIPs). Additionally, its combination with TRAIL inhibited Akt phosphorylation. These results were consistently observed in cells treated with CaM siRNA. We suggested the blockade of CaM could sensitize lung cancer cells to TRAIL-induced apoptosis in at least 2 ways: (i) it can activate death-inducing signaling complex mediated apoptosis by inhibiting TRAIL-induced binding of FLIP and TRAIL-enhanced binding of caspase-8 to FADD; (ii) it can inhibit Akt phosphorylation, consequently leading to decreased expression of anti-apoptotic molecules such as FLIP and members of the inhibitor of apoptosis protein family. This study suggests the combination of CaM antagonists with TRAIL may have the therapeutic potential to overcome the resistance of lung cancers to apoptosis.

• Authors: Mi-kyung Hwang, Yong Ki Min, Seong Hwan Kim
• Journal: Biochemistry and cell biology = Biochimie et biologie cellulaire (Biochem Cell Biol) Vol. 87 Issue 6 Pg. 919-26 (Dec 2009) ISSN: 1208-6002 [Electronic] Canada
• PMID: 19935877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• Calmodulin
• RNA, Small Interfering
• TNF-Related Apoptosis-Inducing Ligand
• fluphenazine-N-mustard
• Proto-Oncogene Proteins c-akt
• Caspases
• Fluphenazine

Topics

• Apoptosis (physiology)
• CASP8 and FADD-Like Apoptosis Regulating Protein (genetics, metabolism)
• Calmodulin (antagonists & inhibitors, genetics, metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Enzyme Activation
• Fluphenazine (analogs & derivatives, chemistry, metabolism)
• Humans
• Lung Neoplasms (metabolism, pathology)
• Molecular Structure
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)