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RIP Kinase Is Involved in Arsenic-Induced Apoptosis in Multiple Myeloma Cells

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RIP Kinase Is Involved in Arsenic-Induced Apoptosis in Multiple Myeloma Cells Apoptosis 2004; 9: 561–571 C 2004 Kluwer Academic Publishers RIP kinase is involved in arsenic-induced apoptosis in multiple myeloma cells O. Bajenova, B. Tang, R. Pearse, R. Feinman, B. H. Childs and J. Michaeli† The Myeloma Service, Division of Hematology-Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA (O. Bajenova, B. Tang, B. H. Childs, J. Michaeli); New York Presbyterian Hospital, Weil Cornell Medical College of Cornell University, New York, NY 10021, USA (R. Pearse); New Jersey Medical School, Newark, NJ 07103, USA (R. Feinman) 1 These studies explore the molecular effect of arsenicals expanding. Recently arsenic trioxide (AT, As2O3) at- on MM cells. Freshly isolated cells derived from patients tracted a lot of attention as a cancer treatment agent. with advanced, chemo-refractory myeloma as well as hu- At physiologically tolerable concentrations (<5 µMin man myeloma cell lines, ARP-1, RPMI-8226 and H929 were exposed to the organic arsenical melarsoprol and plasma), As2O3 causes complete remission of newly diag- to the inorganic compound AT. Both agents potently in- nosed and relapsed acute promyelocytic leukemia cancer duced apoptosis in myeloma cells. Exposure to 1–5 µM patients through a mechanism which involves the degra- AT or melarsoprol for 6 hours suppressed NF-κB DNA dation of the PML-RAR alfa ∼ fusion oncoprotein, gen- binding and enhanced of c-Jun kinase (JNK) activity. Ar- erally expressed in this type of leukemia. AT has been senic also activated caspase-3 resulting in the cleavage of poly (ADP-ribose) polymerase (PARP) and Fas/TNFα utilized as salvage treatment for relapsed and/or refrac- related receptor interacting protein (RIP). In contrast to tory acute promyelocytic leukemia and approved by the reported observations in acute promyelocytic leukemia, FDA in the USA and the SDA in China.2 Moreover, myeloma cell apoptosis was not associated with either arsenicals induce apoptosis in other cell types, indicat- the downregulation of Bcl-2 protein or with alterations in ing that they may also be useful for the treatment of the expression of other Bcl-2 family members, Bax, Bak, 3 4 Bag, and Bcl-xl. This study first shows that arsenic in- hematologic malignancies and solid cancers. For mul- duces apoptotic signaling in MM through the cleavage of tiple myeloma, AT is considered a promising emerging TNFα related receptor interacting protein (RIP). RIP is a therapy.5 It has been successfully used in phase I clin- key downstream protein in FasL/ TNFα /TRAIL induced ical trials in patients with advanced refractory or re- apoptosis and a major antiapoptotic adaptor of pathways lapsed MM in several myeloma centers. Recent clini- through NF-κB and JNK. RIP has not been previously characterized in myeloma. This study supports the hy- cal experiences have shown promising results for MM, pothesis that arsenicals share common mediators (RIP, demonstrating significant efficacy and low incidence of NF-κB, PARP, caspase-3) with death receptor induced complications with AT treatment.6 Importantly, phar- apoptosis. These studies provide an important insight macological concentrations of AT preferentially trig- into the molecular mechanism of AT induced apoptosis ger cancer cell death in the bone marrow of MM pa- and can be used in the development of adjuvant therapy 7,8 for MM, presently an incurable disease. tients while sparing most normal myeloid cells. De- spite the clinical success, the mechanism of the anti- Keywords: apoptosis; arsenic; myeloma; NF-κB; receptor cancer effect of arsenicals on MM cells is still elu- interacting protein (RIP). sive. We first demonstrated that AT induces programmed Introduction cell death (PCD, apoptosis) in patients with advanced re- fractory or relapsed MM, who are resistant to other types Arsenic trioxide has been used as therapeutic agents for of apoptotic stimuli, as well as in human MM cell lines.9 many years in Chinese medicine and its role is rapidly Further it was shown that AT triggers cell cycle arrest associated with the induction of the cyclin-dependent kinase inhibitor P21,10 enhancement of reactive oxygen † 11 Deceased. species, changes in the mitochondrial membrane po- tential 12 and down-regulation of Bcl-2 protein.13 These data highlight the controversy regarding the target pro- Correspondence to: O. Bajenova, BU School of Medicine, Dept. of Surgery, 801 Albany Street Boston, MA 02143, Tel: 617-414- teins and the mechanism that is involved in AT-induced 14 8067, e-mail: [email protected] apoptosis in myeloma cells. Apoptosis · Vol 9 · No 5 · 2004 561 O. Bajenova et al. We hypothesized that arsenicals induce apoptosis mediate domain and an N-terminal kinase domain. Dif- through the death receptors that are overexpressed ferent domains of RIP may be involved in signaling cul- on the surface of myeloma cells. This disease is minating in apoptosis or NF-κB activation. characterized by infiltration of bone marrow with a clone This study will test the hypothesis whether the key of neoplastic plasma cells. Impaired hematopoiesis and elements in the TNFα death receptor induced apopto- reduced production of functional immunoglobulins, as sis, including RIP, NFKB, jun-kinase and caspases are well as the induction of osteolytic lesions, primarily con- involved in AT and melarsoprol initiated cell death in tribute to the morbidity of patients with MM. Malignant MM. Clinical use of AT in myeloma treatment is rapidly plasma cells express very high levels of apoptogenic lig- expanding and in the era of molecular therapies, a better ands, including Fas ligand15,16 and tumor necrosis factor- understanding of the signals resulting in myeloma cell related apoptosis-inducing ligand (TRAIL), which trig- apoptosis will shed the light on potential novel therapeu- ger apoptosis of immature erythroblasts by stimulating tic approaches for this disease which presently has very specific death receptors, namely Fas and the complex limited options. DR4/DR5.17,18 The overexpression of death receptor pro- teins and their ligands is one of the mechanisms by which myeloma cells escape host immune surveillance.16–18 In Materials and methods addition, studies on myeloma bone disease showed that Reagents and cell lines the ligand for receptor activator of nuclear transcription factor-kappaB (RANKL) is over-expressed on MM cells AT was purchased from Sigma Chemical Corp. (St. Louis, 19 and is critical for osteoclast-induced osteolysis. In a MO). Melarsoprol, imelaminophenyl based organic ar- murine model of MM targeting the bone microenviron- senical. Its major clinical application is as an anti- ment by inhibiting the interaction between RANK ligand trypanosomiasis reagent.26 Melarsoprol was purchased and osteoprotegrin not only inhibits the development of from Rhone Poulenc (Strasbourg, FR). Ac-DEVD-CHO myeloma bone disease but also decreases tumor growth was supplied by Calbiochem-Novabiochem Corp. (San 20 and increases survival. RANK/RANKL proteins also Diego, CA). BOC-Asp(Ome)-Fluoromethyl Ketone (B- belong to the TNFα family. There is also an evidence of D-FMK), FK-011 and FK-029 were purchased from En- an immunologic mechanism behind the therapeutic ef- zyme Systems (Product, CA). Oligonucleotides used in 21 fects of AT on myeloma cells. EMSA were synthesized using an ABI oligo-synthesizer We hypothesized that arsenic effects survival of MM (Applied Biosystems, Foster City, CA). GST-c-Jun was cells and induce apoptosis by modulating common me- kindly supplied by Dr. H. Hanafusa (Rockefeller Univer- diators or/and specific enzyme activation events that are sity, NY). The human myeloma cell lines H929, RPM1 involved in the TNFαtrelated cell death. Abnormalities and U266 were obtained from the American Type Culture of the tumor necrosis factor (TNF) family members have Collection (Rockville, MD). The ARP-1 MM cell line was 22 been linked to several human diseases. To date, members kindly supplied by Dr. J. Hardin (University of Arkansas of the TNF family include 26 receptors and 18 ligands. Cancer Research Center, Little Rock). They have pleiotropic biologic functions. Many of these ligand/receptor pairs are involved in the growth regula- tion of normal cells by inducing apoptosis or enhancing Assessment of apoptosis cell survival and proliferation. The signal transduction Cells were cultured at 2× 106/ml in the presence of melar- pathways driven by TNF family members are not fully soprol or AT. Percent cell viability was determined by try- characterized. Acting through distinct surface receptors, pan blue exclusion. Cell number was determined using a all members of TNF family share common cell signaling Coulter Counter (Miami, FL). pathway that mediates the activation of nuclear factor- kappaB (NF-κB) and mitogen-activated protein kinases (e.g. c -jun N-terminal kinase). Regulation of cell growth and activation of NF-κB and of c -jun N-terminal kinase Morphology by the TNF super family is mediated through sequential activation of a set of cell signaling proteins named TNF Following exposure to arsenicals, cells were cytospun onto µ receptor-associated factors, including receptor-interacting glass slides, fixed in methanol, and exposed to 5 g/ml of protein (RIP) and caspases.23 Receptor interacting protein Hoechst stain (Sigma). (RIP) is a death domain kinase, identified through its in- teraction with Fas.24 It is a major antiapoptotic adaptor DNA strand break labeling protein to activate antiapoptotic pathways through NF- κB and JNK.25 The 74 KD RIP contains a C-terminal DNA strand breaks
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