Journal Article

Differential Activation of the c-Jun N-Terminal Kinase Pathway in Arsenite-Induced Apoptosis and Sensitization of Chemically Resistant Compared to Susceptible B-Lymphoma Cell Lines

Donna E. Muscarella and Stephen E. Bloom

in Toxicological Sciences

Volume 68, issue 1, pages 82-92
Published in print July 2002 | ISSN: 1096-6080
Published online July 2002 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/68.1.82
Differential Activation of the c-Jun N-Terminal Kinase Pathway in Arsenite-Induced Apoptosis and Sensitization of Chemically Resistant Compared to Susceptible B-Lymphoma Cell Lines

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Various forms of inorganic arsenic are significant environmental contaminants that have multiple effects on cells, including the induction of apoptotic cell death. Induction of apoptosis in lymphoid cells can mediate immunotoxicity following exposure to chemicals. However, the mechanisms regulating the sensitivity of B-lymphocytes to arsenic-induced apoptosis are not understood. Therefore, we investigated the involvement of key mitogen-activated protein kinase pathways and apoptosis induction by sodium arsenite in a model system of chemically resistant and susceptible B-lymphoma cell lines. These studies revealed a differential requirement for the c-Jun N-terminal kinase (JNK) pathway for apoptosis induction by sodium arsenite in the resistant EW36 versus sensitive ST486 cell lines. Specifically, activation of the JNK pathway was not required for arsenite-induced apoptosis in ST486 cells, whereas JNK pathway activation was always associated with apoptosis induction in EW36 cells. Importantly, we found that EW36 cells, which overexpress the Bcl-2 protein, can be substantially sensitized to arsenite-induced apoptosis by prior exposure to nonlethal hyperthermia. Moreover, pretreatment with an inhibitor of p38 kinase acted synergistically with hyperthermia to further sensitize EW36 cells. The inhibition of p38 prolonged a transient period of JNK phosphorylation that occurred immediately after heat shock treatment and involved the persistent activation of SEK1, one of the kinases upstream of JNK. Significantly, the sensitization of resistant cells is characterized by a lowering of the threshold concentration of arsenite required to activate the JNK pathway and induce apoptosis.

Keywords: sodium arsenite; Burkitt's lymphoma; MAP kinase; JNK; p38; apoptosis; hyperthermia

Journal Article.  9318 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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