Stressful death of T-ALL tumor cells after treatment with the anti-tumor agent Tetrocarcin-A

• Published in: The FASEB journal 2002-08, Vol.16 (10), p.1295-1297
• Main Authors: Tinhofer, Inge, Anether, Gabriele, Senfter, Monika, Pfaller, Kristian, Bernhard, David, Hara, Mitsunobu, Greil, Richard
• Format: Article
• Language: English
• Subjects: Aminoglycosides; Anti-Bacterial Agents - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Caspases - metabolism; Endoplasmic Reticulum - metabolism; Heat-Shock Proteins - biosynthesis; Heat-Shock Proteins - genetics; Humans; Jurkat Cells; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - pathology; Mitochondria - drug effects; Mitochondria - metabolism; Models, Biological; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - physiology; Signal Transduction; Transcription Factors - biosynthesis; Transcription Factors - genetics; Tumor Cells, Cultured; Up-Regulation
• ISSN: 1530-6860
• DOI: 10.1096/fj.02-0020fje

The T-ALL cell lines CCRF-CEM and Jurkat were studied for their sensitivity toward apoptosis induced by tetrocarcin-A (TC-A), an antibacterial and antitumor agent isolated from the actinomycete Micromonospora. This substance promoted cell death via a mitochondrial signaling pathway, that is, by activation of Bid and Bax, loss of the mitochondrial transmembrane potential, release of cytochrome c, and activation of effector caspases, even under conditions of Bcl-2 overexpression. Furthermore, sensitivity to TC-A was not dependent on expression of wild-type caspase-8. In contrast, this apoptotic pathway was inhibited markedly by pretreatment of cells with cycloheximide, an inhibitor of de novo protein synthesis. cDNA microarray chip analysis revealed that TC-A induced a significant up-regulation of members of the heat shock protein family known to be involved in the endoplasmic reticulum (ER)-stress-induced apoptotic program. The activation of caspase-12, the central inducer caspase involved in ER-stress by TC-A treatment, is in concordance with this result. These results show that, in T-ALL cells, TC-A induces an apoptotic machinery via mitochondrial and ER signaling, which is not inhibited by aberrant expression/function of important regulators of death receptor- and drug-induced apoptosis.