Abstract
TNF-related apoptosis-inducing ligand (TRAIL) shares significant homology with CD95 (Fas) ligand and has the ability to induce apoptosis in sensitive cells through a caspase-mediated pathway. We have evaluated the activity of purified human recombinant soluble TRAIL (S-TRAIL, comprising residues 114–281; Biomol, Plymouth Meeting, PA, USA) and a leucine zipper construct of TRAIL (LZ-TRAIL; Immunex, Seattle WA, USA) against myeloma cell lines NCI H929, U266, RPMI 8226, the FasL-sensitive Jurkat T cell ALL line, the lymphoblastoid cell line MC/CAR and primary tumour cells from 16 myeloma patients. Furthermore, we examined the relationship between TRAIL-induced apoptosis and TRAIL receptor expression utilising RT-PCR and flow cytometry. Two of three myeloma cell lines and Jurkat were TRAIL sensitive whereas MC/CAR was relatively resistant. Five of 16 (31%) primary tumours demonstrated ⩾20% reduction in myeloma cells following TRAIL incubation (20–59%). This did not correlate with prior therapy. Four cell lines (two sensitive) and five primary tumours (two sensitive) demonstrated mRNA expression of the intra-cellular death domain containing TRAIL-R1. Variable expression of the two decoy (TRAIL-R3 and R4) and soluble (osteoprotegerin) receptors was seen and this did not correlate with TRAIL resistance. We conclude that myeloma cell expression of death effector receptors for TRAIL is insufficient to confer sensitivity to TRAIL-induced apoptosis but that in a significant minority of patients, irrespective of prior therapy, tumour cells are sensitive to TRAIL. The further investigation of TRAIL as an adjunct to presently available therapies for myeloma is justified.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hjorth M, Holmberg E, Rodjer S, Turesson I, Westin J, Wisloff F . Survival in conventionally treated younger (<60 years) multiple myeloma patients: no improvement during two decades. Nordic Myeloma Study Group (NMSG) Eur J Haematol 1999 62: 271–277
Samson D, Gaminara E, Newland A, Van de Pette J, Kearney J, McCarthy D, Joyner M, Aston L, Mitchell T, Hamon M, Barrett AJ, Evans M . Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma (see comments) Lancet 1989 2: 882–885
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R . A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome (see comments) New Engl J Med 1996 335: 91–97
Bjorkstrand B, Ljungman P, Bird JM, Samson D, Brandt L, Alegre A, Auzanneau G, Blade J, Brunet S, Carlson K . Autologous stem cell transplantation in multiple myeloma: results of the European Group for Bone Marrow Transplantation Stem Cells 1995 13: 140–146
Gura T . How TRAIL kills cancer cells, but not normal cells (news; comment) Science 1997 277: 768
Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC, Lynch DH . Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo (see comments) Nat Med 1999 5: 157–163
Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z, Schwall RH . Safety and antitumor activity of recombinant soluble Apo2 ligand J Clin Invest 1999 104: 155–162
Jo M, Kim T, Seol D, Esplen JE, Dorko K, Billiar TR, Strom SC . Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand Nat Med 2000 6: 564–567
Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM . The receptor for the cytotoxic ligand TRAIL Science 1997 276: 111–113
Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM . An antagonist decoy receptor and a death domain-containing receptor for TRAIL (see comments) Science 1997 277: 815–818
Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A . Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors (see comments) Science 1997 277: 818–821
Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT . TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL EMBO J 1997 16: 5386–5397
MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES . Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL J Biol Chem 1997 272: 25417–25420
Screaton GR, Mongkolsapaya J, Xu XN, Cowper AE, McMichael AJ, Bell JI . TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL Curr Biol 1997 7: 693–696
Degli-Esposti MA, Smolak PJ, Walczak H, Waugh J, Huang CP, DuBose RF, Goodwin RG, Smith CA . Cloning and characterization of TRAIL-R3, a novel member of the emerging TRAIL receptor family J Exp Med 1997 186: 1165–1170
Mongkolsapaya J, Cowper AE, Xu XN, Morris G, McMichael AJ, Bell JI, Screaton GR . Lymphocyte inhibitor of TRAIL (TNF-related apoptosis-inducing ligand): a new receptor protecting lymphocytes from the death ligand TRAIL J Immunol 1998 160: 3–6
Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG . The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain Immunity 1997 7: 813–820
Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P, Ashkenazi A . A novel receptor for Apo2L/TRAIL contains a truncated death domain Curr Biol 1997 7: 1003–1006
Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R, Dodds RA, James IE, Rosenberg M, Lee JC, Young PR . Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL J Biol Chem 1998 273: 14363–14367
Griffith TS, Chin WA, Jackson GC, Lynch DH, Kubin MZ . Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells J Immunol 1998 161: 2833–2840
Snell V, Clodi K, Zhao S, Goodwin R, Thomas EK, Morris SW, Kadin ME, Cabanillas F, Andreeff M, Younes A . Activity of TNF-related apoptosis-inducing ligand (TRAIL) in haematological malignancies Br J Haematol 1997 99: 618–624
Treon SP, Chauhan D, Raje N, Teoh G, Webb I, Anderson KC . Recombinant human TNF-related apoptosis inducing ligand (hu TRAIL) induces apoptosis of human multiple myeloma (MM) cells Blood 1998 10: 634a
Lincz LF, Spencer A . Freshly isolated myeloma cells show variable levels of apoptosis induced by recombinant human TNF-related apoptosis inducing ligand (TRAIL) 1st Annual Scientific Meeting of the Haematology Society of Australia and New Zealand Hobart 1999 p 175
Gazitt Y . TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells Leukemia 1999 13: 1817–1824
Spector DL, Goldman RD, Leinwand LA . Culture and biochemical analysis of cells In Cells, A Laboratory Manual vol 1 Cold Spring Harbor Laboratory Press: New York 1998 pp 15.11–15.12
Spencer A, Xiu-Hua Y, Chase A, Goldman JM, Melo JV . BCR-ABL positive lymphoblastoid cells display limited proliferative capacity under in vitro culture conditions Br J Haematol 1996 94: 654–658
Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliott R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes T . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density Cell 1997 89: 309–319
Griffith TS, Rauch CT, Smolak PJ, Waugh JY, boiani N, Lynch DH, Smith CA, Goodwin RG, Kubin MZ . Functional analysis of TRAIL receptors using monoclonal antibodies J Immunol 1999 162: 2597–2605
Drexler HGD, Dirks WG, MacLeod RAF . False human hematopoietic cell lines: cross-contaminations and misinterpretations Leukemia 1999 13: 1601–1607
Keane MM, Ettenberg SA, Nau MM, Russell EK, Lipkowitz S . Chemotherapy augments TRAIL-induced apoptosis in breast cell lines Cancer Res 1999 59: 734–741
Clodi KW, Wimmer D, Li Y, Goodwin R, Jaeget U, Mann G, Gadner H, Younes A . TRAIL receptor expression and activity of TRAIL in primary B cell acute lymphoblastic leukemia (ALL) cells Blood 1999 94: 301a
Lenhoff S, Hjorth M, Holmberg E, Turesson I, Westin J, Nielsen JL, Wisloff F, Brinch L, Carlson K, Carlsson M, Dahl IM, Gimsing P, Hippe E, Johnsen H, Lamvik J, Lofvenberg E, Nesthus I, Rodjer S . Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population based study Blood 2000 95: 7–11
Acknowledgements
We would like to thank Immunex Corporation for kindly providing LZ-TRAIL and the TRAIL receptor antibodies.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lincz, L., Yeh, TX. & Spencer, A. TRAIL-induced eradication of primary tumour cells from multiple myeloma patient bone marrows is not related to TRAIL receptor expression or prior chemotherapy. Leukemia 15, 1650–1657 (2001). https://doi.org/10.1038/sj.leu.2402251
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402251
Keywords
This article is cited by
-
Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway
Oncogene (2017)
-
sTRAIL-iRGD is a promising therapeutic agent for gastric cancer treatment
Scientific Reports (2017)
-
On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics
Oncogene (2013)
-
Modulation of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptors in a human osteoclast model in vitro
Apoptosis (2012)
-
Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma
British Journal of Cancer (2011)