Abstract
Despite some exciting new leads in molecular pathogenesis, AIDS-defining primary effusion lymphoma (PEL) remains a fatal malignancy. The lack of substantial progress in the management of PEL demands innovative treatment approaches. Targeting intracellular molecules critical to cell survival is one unexplored strategy for treating PEL. Here we show that inhibition of signal transducer and activator of transcription-3 (STAT3) leads to apoptosis in PEL cells. STAT3 is constitutively phosphorylated in PEL cell lines BC-1, BCBL-1, and VG-1. Transduction of dominant-negative STAT3 and pharmacological STAT3 inhibition caused caspase-dependent cell death. Although STAT3 activation is known to induce expression of Bcl-2 family proteins, PEL cell apoptosis was independent of Bcl-2, Bcl-X(L), or Mcl-1 protein expression. Instead, STAT3 inhibition induced transcriptional repression of survivin, a recently identified inhibitor of apoptosis. Forced overexpression of survivin rescued VG-1 cells from apoptosis induced by STAT3 inhibition. Our findings suggest that activated STAT3 signaling directly contributes to malignant progression of PEL by preventing apoptosis, acting through the prosurvival protein survivin. Since constitutive STAT3 activation and survivin expression have been widely documented in different types of cancers, their linkage may extend to many malignancies and be critical to their pathogenesis.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Blotting, Western
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Cell Survival
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Enzyme Inhibitors / pharmacology
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Gene Expression / drug effects*
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Green Fluorescent Proteins
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Herpesviridae Infections
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Herpesvirus 8, Human
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Humans
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Inhibitor of Apoptosis Proteins
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Janus Kinase 2
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Luminescent Proteins / genetics
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Lymphoma, AIDS-Related / metabolism*
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Lymphoma, AIDS-Related / pathology
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Lymphoma, AIDS-Related / virology
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Mice
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Microtubule-Associated Proteins / genetics*
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Mutagenesis
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Neoplasm Proteins
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Phosphorylation
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins*
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Recombinant Fusion Proteins
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor
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Sarcoma, Kaposi
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Signal Transduction*
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Survivin
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / genetics
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Trans-Activators / physiology
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Transfection
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Tumor Cells, Cultured
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Tyrphostins / pharmacology
Substances
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BIRC5 protein, human
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DNA-Binding Proteins
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Enzyme Inhibitors
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Inhibitor of Apoptosis Proteins
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Luminescent Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Survivin
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Green Fluorescent Proteins
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Jak2 protein, mouse
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Janus Kinase 2