title: Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute lymphoblastic leukemia.
abstract: Resistance to apoptosis remains a significant problem in drug resistance and treatment failure in malignant disease. NO-aspirin is a novel drug that has efficacy against a number of solid tumours, and can inhibit Wnt signaling, and although we have shown Wnt signaling to be important for acute lymphoblastic leukemia (ALL) cell proliferation and survival inhibition of Wnt signaling does not appear to be involved in the induction of ALL cell death. Treatment of B lineage ALL cell lines and patient ALL cells with NO-aspirin induced rapid apoptotic cell death mediated via the extrinsic death pathway. Apoptosis was dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC) incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1). There was no measurable increase in TNF-R1 or TNF-α in response to NO-aspirin, suggesting that the process was ligand-independent. Consistent with this, expression of silencer of death domain (SODD) was reduced following NO-aspirin exposure and lentiviral mediated shRNA knockdown of SODD suppressed expansion of transduced cells confirming the importance of SODD for ALL cell survival. Considering that SODD and caspase-10 are frequently over-expressed in ALL, interfering with these proteins may provide a new strategy for the treatment of this and potentially other cancers.
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Adam
authors: A
authors: Cisterne
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Rana
authors: R
authors: Baraz
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Naveed I
authors: NI
authors: Khan
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Robert
authors: R
authors: Welschinger
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Jordan
authors: J
authors: Basnett
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Carina
authors: C
authors: Fung
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Helen
authors: H
authors: Rizos
authors: Blood and Marrow Transplant Service, Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia.
authors: Kenneth F
authors: KF
authors: Bradstock
authors: Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.
authors: Linda J
authors: LJ
authors: Bendall
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D053455:Caspase 10 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D019169:Jurkat Cells; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C116906:BAG4 protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D053455:Caspase 10