期刊
ONCOGENE
卷 24, 期 3, 页码 419-430出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1208212
关键词
HTLV-I; leukemia; lymphoma; treatment; proteasome inhibitors; PS-341
HTLV-I associated adult T-cell leukemia (ATL) and HTLV-I-negative peripheral T-cell lymphomas are associated with poor prognosis. Using pharmacological concentrations of the proteasome inhibitor PS-341, we demonstrate inhibition of cell proliferation and induction of apoptosis in fresh ATL cells, HTLV-I transformed and HTLV-I-negative malignant T cells, while normal resting or activated T lymphocytes were resistant. Combination of PS-341 and doxorubicin or etoposide resulted in an additive growth inhibition. In HTLV-I-negative malignant cells, PS-341 treatment significantly downregulated the antiapoptotic protein X-IAP and to a lesser extent c-IAP-1 and bcl-XL and resulted in caspase-dependent apoptosis. In HTLV-I transformed cells, the inhibition of the proteasomal degradation of Tax by PS-341 likely explains the relative protection of HTLV-I infected cells against caspase-dependent apoptosis. PS-341 treatment of these cells stabilized IkappaBalpha, IkappaBbeta, IkappaBepsilon, p21, p27 and p53 proteins and selectively inhibited Rel-A DNA binding NF-kappaB complexes. In both HTLV-I-positive and -negative cells, PS-341 treatment induced ceramide accumulation that correlated with apoptosis. We conclude that PS-341 affects multiple pathways critical for the survival of HTLV-I-positive and -negative malignant T cells supporting a potential therapeutic role for PS-341 in both ATL and HTLV-I-negative T-cell lymphomas, whether alone or in combination with chemotherapy.
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