PATHOLOGY & ONCOLOGY RESEARCHVol. 13 No. 4, 2007

 Article

Inhibition of Novel Protein Kinase C-epsilon Augments TRAIL-induced Cell Death in A549 Lung Cancer Cells

Matthias FELBER1, Jürgen SONNEMANN1, James F BECK2

1Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany
2Department of Pediatric Oncology/Hematology, Ernst Moritz Arndt University, Greifswald, Germany

 

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has great potential for cancer treatment since it provokes cell death in most tumor cells while leaving most normal cells unscathed. Some cancers, however, show resistance to TRAIL, indicating that TRAIL alone may be insufficient for cancer therapy. Here we studied whether the apoptotic susceptibility of A549 non-small cell lung cancer cells could be modulated by inhibiting protein kinase C (PKC). We show that an inhibitor with preference for novel PKC isozymes, NPC 15437, significantly augmented TRAIL sensitivity of A549 cells, as judged by assessing cell death and mitochondrial membrane potential. Likewise, NPC 15437 also significantly potentiated the responsiveness of DAOY medulloblastoma cells to TRAIL. In contrast, an inhibitor with preference for conventional PKC isozymes, Gö6976, did not augment TRAIL sensitivity of A549 cells. To further specify the PKC isozyme responsible for TRAIL sensitization, we used a peptide inhibitor with selectivity for the novel PKC isozyme epsilon, myr-PKC-epsilon V1-2. The inhibition of PKC-epsilon resulted in a significant amplification of the cytotoxic activity of TRAIL in A549 cells. Altogether, our study provides evidence for a considerable role of PKC-epsilon in the apoptotic responsiveness of A549 lung cancer cells, and possibly other malignancies, to TRAIL. Pathology & Oncology Research, Vol 13, Nr 4, 295-301, 2007

Key words: lung cancer; medulloblastoma; NPC 15437; protein kinase C-epsilon; TNF; TRAIL


Received: Mar 5, 2007; accepted: Sep 20, 2007
Correspondence: James F BECK, Department of Pediatric Oncology/Hematology, Ernst Moritz Arndt University, Soldmannstr. 15 Greifswald D-17475, Germany; Tel: +49-3834-866324, Fax: +49-3834-866323; E-mail: beck@uni-greifswald.de

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