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Cellular resistance to vincristine suppresses NF-κB activation and apoptosis but enhances c-Jun-NH2-terminal protein kinase activation by tumor necrosis factor

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Abstract

Tumor necrosis factor (TNF) is a pleiotropic cytokine that potentiates the cytotoxic effects of chemotherapeutic drugs. Although emergence of resistance to chemotherapeutic drugs is a major problem in cancer therapy, its mechanism is incompletely understood. Recently, activation of a nuclear transcription factor NF-κB has been reported to be a signal for anti-apoptosis. In this report, we investigated the effect of TNF on activation of NF-κB, c-Jun N-terminal kinase (JNK), and apoptosis in vincristine-resistant human histiocytic lymphoma U937-VR cells. Unlike the parent clone (U937-VS), no activation of caspase-3, known to be required for apoptosis, was found in vincristine-resistant cells on exposure to vincristine. These cells were also more resistant than U-937-VS cells to doxorubicin, daunomycin, and taxol. TNF-induced NF-κB activation, IκB α degradation, and nuclear translocation of p65 were all found to be highly suppressed in the U-937-VR cells. NF-κB activation by LPS, H 2 O 2 , and okadaic acid was also suppressed. However, vincristine resistance enhanced TNF-induced JNK activation. When examined for apoptosis, vincristine resistance suppressed the cytotoxic effects and caspase-3 activation by TNF. The resistant phenotype in U937-VR cells was independent of the expression of the apoptosis-suppressor, Bcl-2. Thus, overall these results indicate that vincristine resistance correlates with suppression of NF-κB activation, cytotoxicity, and caspase-3 activation but enhancement of JNK activation by TNF.

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Authors and Affiliations

  1. Cytokine Research Laboratory, Department of Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    D. K. Giri & B. B. Aggarwal

  2. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, 02912

    P. Pantazis

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Giri, D.K., Pantazis, P. & Aggarwal, B.B. Cellular resistance to vincristine suppresses NF-κB activation and apoptosis but enhances c-Jun-NH2-terminal protein kinase activation by tumor necrosis factor. Apoptosis 4, 291–301 (1999). https://doi.org/10.1023/A:1026413111733

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