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Stressful death of T‐ALL tumor cells following treatment with the antitumor agent Tetrocarcin‐A
Author(s) -
Tinhofer Inge,
Anether Gabriele,
Senfter Monika,
Pfaller Kristian,
Bernhard David,
Hara Mitsunobu,
Greil Richard
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0020fje
Subject(s) - apoptosis , jurkat cells , microbiology and biotechnology , unfolded protein response , cycloheximide , programmed cell death , endoplasmic reticulum , caspase , caspase 8 , caspase 9 , cytochrome c , intrinsic apoptosis , signal transduction , chemistry , biology , mitochondrion , t cell , protein biosynthesis , biochemistry , immunology , immune system
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)‐stressinduced 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 TALL 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 druginduced apoptosis.