Abstract
Cancer cell resistance to chemotherapy may be mediated by defects in apoptotic pathways. A prior study showed that in vivo apoptosis of Acute Lymphoblastic Leukemia (ALL) blasts in response to chemotherapy could occur through diverse pathways including both p53-dependent and -independent mechanisms. In this study we investigated the apoptotic response in more detail by using a panel of ALL cell lines that differed in respect to p53 status. Upon exposure to a uniform stimulus, expression of apoptotic proteins, including the effector caspase-3, varied among ALL cell lines partly depending on p53 transcriptional activity and caspase-8 activation. Although the expression and contribution to apoptosis differed among known members of the apoptotic pathway, apoptosis was universally mediated by mitochondrial depolarization. The NFκB pathway was activated in response to chemotherapy but NFκB inhibition appeared to not influence chemosensitivity. This study further documents the highly variable nature of cell death programs in ALL and provides the foundation for cell death pathway modulation to improve ALL cure rates without increasing chemotherapy-related toxicity.
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References
Pui CH, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 354:166–178
Ferri KF, Kroemer G (2001) Organelle-specific initiation of cell death pathways. Nature Cell Biol 3:E255–E263
Kim R, Tanabe K, Uchida Y, Emi M, Inoue H, Toge T (2002) Current status of the molecular mechanisms of anticancer drug-induced apoptosis. Cancer Chemother Pharmacol 50:343–352
Schimmer AD, Hedley DW, Penn LZ, Minden MD (2001) Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view. Blood 98:3541–3553
Liu T, Raetz E, Moos PJ et al (2002) Diversity of the apoptotic response to chemotherapy in childhood leukemia. Leukemia 16:223–232
Jonveaux P, Berger R (1991) Infrequent mutations in the p53 gene in primary human T-cell acute lymphoblastic leukemia. Leukemia 5:839–840
Fenaux P, Jonveaux P, Quiquandon I et al (1992) Mutations of the p53 gene in B-cell acute lymphoblastic leukemia: A report on 60 cases. Leukemia 6:42–46
Turco MC, Romano MF, Petrella A, Bisogni R, Tassone P, Venuta S (2004) NF-κB/Rel-mediated regulation of apoptosis in hematologic malignancies and normal hematopoietic progenitors. Leukemia 18:11–17
Shehata MF (2005) Rel/Nuclear factor-kappa B apoptosis pathways in human cervical cancer cells. Cancer Cell Int 5:10–22
Karin M, Yamamoto Y, Wang QM (2004) The IKK NF-κB system: A treasure trove for drug development. Nat Rev Drug Discov 3:17–26
Amiri KI, Horton LW, LaFleur BJ, Sosman JA, Richmond A (2004) Augmenting chemosensitivity of malignant melanoma tumors via proteasome inhibition: implication for Bortezomib (VELCADE, PS-341) as a therapeutic agent for malignant melanoma. Cancer Res 64:4912–4918
Zhou M, Gu L, Li F, Zhu Y, Woods WG, Findley HW (2002) DNA damage induces a novel p53-Survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells. J Pharmacol Exp Ther 303:124–131
Zhou M, Yeager AM, Smith SD, Findley HW (1995) Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene. Blood 85:1608–1614
Mitsiades N, Mitsiades CS, Poulaki V et al (2002) Biologic sequelae of nuclear factor-κB blockade in multiple myeloma: therapeutic applications. Blood 99:4079–4086
Bargonetti J, Manfredi JJ (2002) Multiple roles of the tumor suppressor p53. Curr Opin Oncol 14:86–91
Marchenko ND, Zaika A, Moll UM (2000) Death signal-induced localization of p53 protein to mitochondria. J Biol Chem 275:16202–16212
Herr I, Wilhelm D, Bohler T, Angel P, Debatin KM (1997) Activation of CD95 (APO-1/Fas) signaling by ceramide mediates cancer therapy-induced apoptosis. EMBO J 16:6200–6208
Fulda S, Susin SA, Kroemer G, Debatin KM (1998) Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 58:4453–4460
Engels IH, Stepczynska A, Stroh C et al (2000) Caspase-8/FLICE function as an executioner caspase in anticancer drug-induced apoptosis. Oncogene 19:4563–4573
Chandra D, Choy G, Deng X, Bhatia B, Daniel P, Tang DG (2004) Association of active caspase 8 with the mitochondrial membrane during apoptosis: potential roles in cleaving BAP31 and caspase 3 and mediating mitochondrion-endoplasmic reticulum cross talk in etoposide-induced cell death. Mol Cell Biol 24:6592–6607
Marks DI, Kurz BW, Link MP et al (1996) High incidence of potential p53 inactivation in poor outcome childhood acute lymphoblastic leukemia at diagnosis. Blood 87:1155–1161
Chen F, Castranova V, Shi X (2001) New insights into the role of nuclear factor-κB in cell growth regulation. Am J Perinatol 159:387–397
Haarman EG, Kaspers GJ, Pieters R et al (1999) BCL-2 expression in childhood leukemia versus spontaneous apoptosis, drug induced apoptosis, and in vitro drug resistance. Adv Exp Med Biol 457:325–333
Blade J, Cibeira MT, Rosinol L (2005) Bortezomib: a valuable new antineoplastic strategy in multiple myeloma. Acta Oncol 44:440–448
Kasuga C, Ebata T, Kayagaki N et al (2004) Sensitization of human glioblastomas to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by NF-κB inhibitors. Cancer Sci 95:840–844
Starenki D, Namba H, Saenko V, Ohtsuru A, Yamashita S (2004) Inhibition of nuclear factor-κB cascade potentiates the effect of a combination treatment of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 89:410–418
Meli M, D’alessandro N, Tolomeo M, Rausa L, Notarbartolo M, Dusonchet L (2003) NF-κB inhibition restores sensitivity to Fas-mediated apoptosis in lymphoma cell lines. Ann NY Acad Sci 1010:232–236
Schrappe M, Reiter A, Zimmermann M et al (2000) Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Leukemia 14:2205–2222
Karpinich NO, Tafani M, Rothman RJ, Russo MA, Farber JL (2002) The course of etoposide-induced apoptosis from damage to DNA and p53 activation to mitochondrial release of cytochrome c. J Biol Chem 277:16547–16552
Greenstein S, Krett NL, Kurosawa Y et al (2003) Characterization of the MM.1 human multiple myeloma (MM) cell lines: a model system to elucidate the characteristics, behavior, and signaling of steroid-sensitive and -resistant MM cells. Exp Hematol 31:271–282
Sansome C, Zaika A, Marchenko ND, Moll UM (2001) Hypoxia death stimulus induces translocation of p53 protein to mitochondria. FEBS Lett 488:110–115
Mihara M, Erster S, Zaika A et al (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11:577–590
Chipuk JE, Kuwana T, Bouchier-Hayes L et al (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014
Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164
An WG, Hwang SG, Trepel JB, Blagosklonny MV (2000) Protease inhibitor-induced apoptosis: accumulation of wt p53, p21WAF1/CIP1, and induction of apoptosis are independent markers of proteasome inhibition. Leukemia 14:1276–1283
Richardon P (2003) Clinical update: proteasome inhibitors in hematologic malignancies. Cancer Treat Rev 29 (Suppl 1):33–39
Wesselborg S, Engels IH, Rossmann E, Los M, Schulze-Osthoff K (1999) Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood 93:3053–3063
Lin CF, Chen CL, Chang WT et al (2004) Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide- and etoposide-induced apoptosis. J Biol Chem 279:40755–40761
Schwartz SA, Hernandez A, Evers BM (1999) The role of NF-κB/IκB proteins in cancer: implications for novel treatment strategies. Surg Oncol 8:143–153
Richmond A (2002) NF-κB, chemokine gene transcription and tumour growth. Nat Rev Immunol 2:664–674
Bauer JA, Trask DK, Kumar B et al (2005) Reversal of cisplatin resistance with a BH3 mimetic, (–)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL. Mol Cancer Ther 4:1096–1104
Cohen GM (1997) Caspases: the executioners of apoptosis. Biochem J 326:1–16
Susin SA, Lorenzo HK, Zamzami N et al (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446
Vahsen N, Candé C, Brièreet JJ et al (2004) AIF deficiency compromises oxidative phosphorylation. EMBO J 23:4679–4689
Chen L, Willis SN, Wei A et al (2005) Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393–403
Melino GF, Bernassola M, Ranalli K et al (2004) p73 induces apoptosis via PUMA transactivation and Bax mitochondrial translocation. J Biol Chem 279:8076–8083
Casale F, Addeo R, D’Angelo V et al (2003) Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia. Int J Oncol 22:123–128
Jaattela M, Tschopp J (2003) Caspase-independent cell death in T lymphocytes. Nature Immunol 4:416–423
Ishitsuka K, Hideshima T, Hamasaki M et al (2005) Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and –independent apoptosis. Blood 106:1794–1800
Carter BZ, Kornblau SM, Tsao T et al (2003) Caspase-independent cell death in AML: caspase inhibition in vitro with pan-caspase inhibitors or in vivo by XIAP or Survivin does not affect cell survival or prognosis. Blood 102:4179–4186
Stanglmaier M, Reis S, Hallek M (2004) Rituximab and alemtuzumab induce a nonclassic, caspase-independent apoptotic pathway in B-lymphoid cell lines and in chronic lymphocytic leukemia cells. Ann Hematol 83:634–645
Martins LM, Iaccarino I, Tenev T et al (2002) The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif. J Biol Chem 277:439–444
Gross A, McDonnell JM, Korsmeyer SJ (1999) Bcl-2 family members and the mitochondria in apoptosis. Genes Dev 13:1899–1911
Ruvolo PP, Deng X, May WS (2001) Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia 15:515–522
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Min, DJ., Moskowitz, N.P., Brownstein, C. et al. Diverse pathways mediate chemotherapy-induced cell death in acute lymphoblastic leukemia cell lines. Apoptosis 11, 1977–1986 (2006). https://doi.org/10.1007/s10495-006-0081-1
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DOI: https://doi.org/10.1007/s10495-006-0081-1