RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells Journal Article


Authors: Bajenova, O.; Tang, B.; Pearse, R.; Feinman, R.; Childs, B. H.; Michaeli, J.
Article Title: RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells
Abstract: These studies explore the molecular effect of arsenicals on MM cells. Freshly isolated cells derived from patients with advanced, chemo-refractory myeloma as well as human myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and to the inorganic compound AT. Both agents potently induced apoptosis in myeloma cells. Exposure to 1-5 μM AT or melarsoprol for 6 hours suppressed NF-κB DNA binding and enhanced of c-Jun kinase (JNK) activity. Arsenic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNFα related receptor interacting protein (RIP). In contrast to reported observations in acute promyelocytic leukemia, myeloma cell apoptosis was not associated with either the downregulation of Bcl-2 protein or with alterations in the expression of other Bcl-2 family members, Bax, Bak, Bag, and Bcl-xl. This study first shows that arsenic induces apoptotic signaling in MM through the cleavage of TNFα related receptor interacting protein (RIP). RIP is a key downstream protein in FasL/ TNFα /TRAIL induced apoptosis and a major antiapoptotic adaptor of pathways through NF-κB and JNK. RIP has not been previously characterized in myeloma. This study supports the hypothesis that arsenicals share common mediators (RIP, NF-κB, PARP, caspase-3) with death receptor induced apoptosis. These studies provide an important insight into the molecular mechanism of AT induced apoptosis and can be used in the development of adjuvant therapy for MM, presently an incurable disease.
Keywords: signal transduction; controlled study; unclassified drug; human cell; cell survival; cell division; protein bcl 2; apoptosis; multiple myeloma; stress activated protein kinase; protein degradation; fas antigen; cell line; immunoglobulin enhancer binding protein; protein interaction; caspase 3; enzyme activation; enzyme activity; protein bcl xl; caspases; cell line, tumor; arsenic trioxide; dna; tumor necrosis factor alpha; tumor necrosis factor related apoptosis inducing ligand; nf-kappa b; tumor cell line; promyelocytic leukemia; cell isolation; down regulation; dna binding; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; myeloma; hypothesis; protein bax; nf-κb; receptor protein; protein bak; arsenic; humans; human; priority journal; article; receptor interacting protein (rip); bag 1 protein; melarsoprol; receptor interacting protein
Journal Title: Apoptosis
Volume: 9
Issue: 5
ISSN: 1360-8185
Publisher: Springer  
Date Published: 2004-09-01
Start Page: 561
End Page: 571
Language: English
DOI: 10.1023/b:appt.0000038030.47068.49
PROVIDER: scopus
PUBMED: 15314284
DOI/URL:
Notes: Apoptosis -- Cited By (since 1996):12 -- Export Date: 16 June 2014 -- CODEN: APOPF -- Source: Scopus
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MSK Authors
  1. Barrett H Childs
    74 Childs
  2. Baiqing Tang
    14 Tang