JWA is required for arsenic trioxide induced apoptosis in HeLa and MCF-7 cells via reactive oxygen species and mitochondria linked signal pathway.
Arsenic trioxide, emerging as a standard therapy for refractory acute promyelocytic leukemia, induces apoptosis in a variety of malignant cell lines. JWA, a novel retinoic acid-inducible gene, is known to be involved in apoptosis induced by various agents, for example, 12-O-tetradecanoylphorbol 13-acetate, N-4-hydroxy-phenyl-retinamide and arsenic trioxide. However, the molecular mechanisms underlying how JWA gene is functionally involved in apoptosis remain largely unknown. Herein, our studies demonstrated that treatment of arsenic trioxide produced apoptosis in HeLa and MCF-7 cells in a dose-dependent manner and paralleled with increased JWA expression. JWA expression was dependent upon generation of intracellular reactive oxygen species induced by arsenic trioxide. Knockdown of JWA attenuated arsenic trioxide induced apoptosis, and was accompanied by significantly reduced activity of caspase-9, enhanced Bad phosphorylation and inhibited MEK1/2, ERK1/2 and JNK phosphorylations. Arsenic trioxide induced loss of mitochondrial transmembrane potential was JWA-dependent. These findings suggest that JWA may serve as a pro-apoptotic molecule to mediate arsenic trioxide triggered apoptosis via a reactive oxygen species and mitochondria-associated signal pathway.
Zhou
Jinhong
J
Department of Molecular Cell Biology and Toxicology, Institute of Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, People's Republic of China.
Ye
Jian
J
Zhao
Xiaojia
X
Li
Aiping
A
Zhou
Jianwei
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D026901:Membrane Transport Proteins; D008928:Mitochondria / Q000187:drug effects*; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects
C484566:ARL6IP5 protein, human; D000970:Antineoplastic Agents; D001152:Arsenicals; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; D000077237:Arsenic Trioxide