Induction of a TRAIL-mediated suicide program by interferon alpha in primary effusion lymphoma.
Gammaherpes viruses are often detected in lymphomas arising in immunocompromised patients. We have found that Azidothymidine (AZT) alone induces apoptosis in Epstein Barr Virus (EBV) positive Burkitt's lymphoma (BL) cells but requires interferon alpha (IFN-alpha) to induce apoptosis in Human Herpes Virus Type 8 (HHV-8) positive Primary Effusion Lymphomas (PEL). Our analysis of a series of AIDS lymphomas revealed that IFN-alpha selectively induced very high levels of the Death Receptor (DR) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in HHV-8 positive PEL lines and primary tumor cells whereas little or no induction was observed in primary EBV+ AIDS lymphomas and EBV-Burkitt's lines. AZT and IFN-alpha mediated apoptosis in PEL was blocked by stable overexpression of dominant negative Fas Associated Death Domain (FADD), decoy receptor 2 (DcR2), soluble TRAIL receptor fusion proteins (DR-4 and DR-5) and thymidine. Trimeric TRAIL (in place of IFN-alpha) similarly synergized with AZT to induce apoptosis in HHV-8 positive PEL cells. This is the first demonstration that IFN-alpha induces functional TRAIL in a malignancy that can be exploited to effect a suicide program. This novel antiviral approach to Primary Effusion lymphomas is targeted and may represent a highly effective and relatively non-toxic therapy.
Toomey
N L
NL
Department of Medicine, University of Miami School of Medicine, Miami, Florida, FL 33136, USA.
Deyev
V V
VV
Wood
C
C
Boise
L H
LH
Scott
D
D
Liu
L H
LH
Cabral
L
L
Podack
E R
ER
Barber
G N
GN
Harrington
W J
WJ
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; D001704:Biopolymers; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000150:complications; D005047:Etoposide / Q000494:pharmacology; D044943:Fatty Acid Desaturases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2; D015658:HIV Infections / Q000150:complications; D006566:Herpesviridae Infections / Q000150:complications; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D019288:Herpesvirus 8, Human / Q000302:isolation & purification; D006801:Humans; D016867:Immunocompromised Host; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D016483:Lymphoma, AIDS-Related / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013936:Thymidine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D014412:Tumor Virus Infections / Q000150:complications; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use; D051020:bcl-X Protein
D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D029681:Arabidopsis Proteins; C494811:BCL2L1 protein, human; D001704:Biopolymers; D007155:Immunologic Factors; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D015215:Zidovudine; D005047:Etoposide; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis; D003546:Cysteine Endopeptidases; D013936:Thymidine