Role of Bim in diallyl trisulfide-induced cytotoxicity in human cancer cells.
The aim of this study was to investigate the effect of garlic constituent diallyl trisulfide (DATS) on the cell-death signaling pathway in a human breast cell line (MDA-MB-231). We observed that DATS (10-100 µM) treatment resulted in dose- and time-dependent cytotoxicity. Treatment of MDA-MB-231 cells with a cytotoxicity inducing concentration of DATS (50-80 µM) resulted in an increase in the intracellular level of reactive oxygen species (ROS). Data from assay with MitoSOX(TM) Red reagent suggest that mitochondria are the main source of ROS generation during DATS treatment. DATS-induced oxidative stress was detected through glutaredoxin (GRX), a redox-sensing molecule, and subsequently GRX was dissociated from apoptosis signal-regulating kinase 1 (ASK1). Dissociation of GRX from ASK1 resulted in the activation of ASK1. ASK1 activated a downstream signal transduction JNK (c-Jun N-terminal kinase)-Bim pathway. SP600125, a JNK inhibitor, inhibited DATS-induced Bim phosphorylation and protected cells from DATS-induced cytotoxicity. Our results indicate that the cytotoxicity caused by DATS is mediated by the generation of ROS and subsequent activation of the ASK1-JNK-Bim signal transduction pathway in human breast carcinoma MDA-MB-231 cells.
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Byeong-Chel
BC
Lee
Bae-Hang
BH
Park
Seog-Young
SY
Kim
Yong J
YJ
Lee
D000498:Allyl Compounds / Q000494:pharmacology / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005737:Garlic / Q000737:chemistry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013440:Sulfides / Q000494:pharmacology / Q000633:toxicity*
D000498:Allyl Compounds; D000970:Antineoplastic Agents; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D013440:Sulfides; C042577:diallyl trisulfide; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human