Influence of Casein Kinase II in Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis in Human Rhabdomyosarcoma Cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis via the death receptors DR4 and DR5 in transformed cells in vitro and exhibits potent antitumor activity in vivo with minor side effects. Protein kinase casein kinase II (CK2) is increased in response to diverse growth stimuli and is aberrantly elevated in a variety of human cancers. Rhabdomyosarcoma tumors are the most common soft-tissue sarcoma in childhood. In this investigation, we demonstrate that CK2 is a key survival factor that protects tumor cells from TRAIL-induced apoptosis. We have demonstrated that inhibition of CK2 phosphorylation events by 5,6-dichlorobenzimidazole (DRB) resulted in dramatic sensitization of tumor cells to TRAIL-induced apoptosis. CK2 inhibition also induced rapid cleavage of caspase-8, -9, and -3, as well as the caspase substrate poly(ADP-ribose) polymerase after TRAIL treatment. Overexpression of Bcl-2 protected cells from TRAIL-induced apoptosis in the presence of the CK2 inhibitor. Death signaling by TRAIL in these cells was Fas-associated death domain and caspase dependent because dominant negative Fas-associated death domain or the cowpox interleukin 1β-converting enzyme inhibitor protein cytokine response modifier A prevented apoptosis in the presence of DRB. Analysis of death-inducing signaling complex (DISC) formation demonstrated that inhibition of CK2 by DRB increased the level of recruitment of procaspase-8 to the DISC and enhanced caspase-8-mediated cleavage of Bid, thereby increasing the release of the proapoptotic factors cytochrome c, HtrA2/Omi, Smac/DIABLO, and apoptosis inducing factor (AIF) from the mitochondria, with subsequent degradation of X-linked inhibitor of apoptosis protein (XIAP). To further interfere with CK2 function, JR1 and Rh30 cells were transfected with either short hairpin RNA targeted to CK2α or kinase-inactive CK2α (K68M) or CK2α′ (K69M). Data show that the CK2 kinase activity was abrogated and that TRAIL sensitivity in both cell lines was increased. Silencing of CK2α expression with short hairpin RNA was also associated with degradation of XIAP. These findings suggest that CK2 regulates TRAIL signaling in rhabdomyosarcoma by modulating TRAIL-induced DISC formation and XIAP expression.

[1]  M. Andreeff,et al.  Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia , 2003, Leukemia.

[2]  J. Houghton,et al.  Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C. , 2003, Cancer research.

[3]  I. Jeremias,et al.  TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB , 2003, Oncogene.

[4]  J. Houghton,et al.  A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells , 2003, Cell Death and Differentiation.

[5]  A. Ashkenazi,et al.  Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. , 2003, Cytokine & growth factor reviews.

[6]  J Downward,et al.  Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain , 2002, Cell Death and Differentiation.

[7]  R. Dietz,et al.  Phosphorylation by protein kinase CK2: a signaling switch for the caspase-inhibiting protein ARC. , 2002, Molecular cell.

[8]  R. Ravi,et al.  Sensitization of tumor cells to Apo2 ligand/TRAIL-induced apoptosis by inhibition of casein kinase II. , 2002, Cancer research.

[9]  L. Pinna,et al.  Protein kinase CK2 inhibitor 4,5,6,7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. , 2002, The Biochemical journal.

[10]  K. Ahmed,et al.  Joining the cell survival squad: an emerging role for protein kinase CK2. , 2002, Trends in cell biology.

[11]  K. Ahmed,et al.  Response of cancer cells to molecular interruption of the CK2 signal , 2001, Molecular and Cellular Biochemistry.

[12]  R. Kraft,et al.  Targeting of the transcription factor Max during apoptosis: phosphorylation-regulated cleavage by caspase-5 at an unusual glutamic acid residue in position P1. , 2001, The Biochemical journal.

[13]  J. Martinou,et al.  Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. , 2001, Molecular cell.

[14]  R. Cardiff,et al.  Protein kinase CK2 in mammary gland tumorigenesis , 2001, Oncogene.

[15]  L. Jia,et al.  Trail-induced apoptosis in Type I leukemic cells is not enhanced by overexpression of bax. , 2001, Biochemical and biophysical research communications.

[16]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[17]  R. K Srivastava,et al.  Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways , 2001, Oncogene.

[18]  Chuan-hai Guo,et al.  A Potential Role of Nuclear Matrix-associated Protein Kinase CK2 in Protection against Drug-induced Apoptosis in Cancer Cells* , 2001, The Journal of Biological Chemistry.

[19]  M. Sarker,et al.  Activation of protein kinase C inhibits TRAIL-induced caspases activation, mitochondrial events and apoptosis in a human leukemic T cell line , 2001, Cell Death and Differentiation.

[20]  Jean X. Jiang,et al.  Regulation of Lens Connexin 45.6 by Apoptotic Protease, Caspase-3 , 2001, Cell communication & adhesion.

[21]  J. Houghton,et al.  Pediatric rhabdomyosarcoma cell lines are resistant to Fas-induced apoptosis and highly sensitive to TRAIL-induced apoptosis. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  V. Mootha,et al.  tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. , 2000, Genes & development.

[23]  P. Houghton,et al.  P53 mutation and MDM2 amplification frequency in pediatric rhabdomyosarcoma tumors and cell lines. , 2000, Medical and pediatric oncology.

[24]  K. Ahmed,et al.  Antisense oligonucleotides against protein kinase CK2‐α inhibit growth of squamous cell carcinoma of the head and neck in vitro , 2000, Head & neck.

[25]  P. Krammer,et al.  Tumor necrosis factor-related apoptosis-inducing ligand retains its apoptosis-inducing capacity on Bcl-2- or Bcl-xL-overexpressing chemotherapy-resistant tumor cells. , 2000, Cancer research.

[26]  Seamus J. Martin,et al.  Failure of Bcl‐2 to block cytochrome c redistribution during TRAIL‐induced apoptosis , 2000, FEBS letters.

[27]  B. Gliniak,et al.  Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. , 1999, Cancer research.

[28]  G. Niehans,et al.  Subcellular immunolocalization of protein kinase CK2 in normal and carcinoma cells. , 1999, The international journal of biochemistry & cell biology.

[29]  D. Lawrence,et al.  Safety and antitumor activity of recombinant soluble Apo2 ligand. , 1999, The Journal of clinical investigation.

[30]  C. Rauch,et al.  Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo , 1999, Nature Medicine.

[31]  D Orlic,et al.  Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis. , 1999, Blood.

[32]  S. Korsmeyer,et al.  Caspase Cleaved BID Targets Mitochondria and Is Required for Cytochrome c Release, while BCL-XL Prevents This Release but Not Tumor Necrosis Factor-R1/Fas Death* , 1999, The Journal of Biological Chemistry.

[33]  T. Griffith,et al.  TRAIL: a molecule with multiple receptors and control mechanisms. , 1998, Current opinion in immunology.

[34]  T. Griffith,et al.  Intracellular regulation of TRAIL-induced apoptosis in human melanoma cells. , 1998, Journal of immunology.

[35]  V. Dixit,et al.  Death receptors: signaling and modulation. , 1998, Science.

[36]  Junying Yuan,et al.  Cleavage of BID by Caspase 8 Mediates the Mitochondrial Damage in the Fas Pathway of Apoptosis , 1998, Cell.

[37]  J. Houghton,et al.  Expression of genes that regulate Fas signalling and Fas-mediated apoptosis in colon carcinoma cells , 1998, Cell Death and Differentiation.

[38]  J C Reed,et al.  IAPs block apoptotic events induced by caspase‐8 and cytochrome c by direct inhibition of distinct caspases , 1998, The EMBO journal.

[39]  D. Goeddel,et al.  FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. , 1998, Science.

[40]  P. Scheurich,et al.  Dominant-negative FADD inhibits TNFR60-, Fas/Apo1- and TRAIL-R/Apo2-mediated cell death but not gene induction , 1998, Current Biology.

[41]  C. Thompson,et al.  Human IAP-Like Protein Regulates Programmed Cell Death Downstream of Bcl-xL and Cytochrome c , 1998, Molecular and Cellular Biology.

[42]  J. Tschopp,et al.  TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. , 1997, Immunity.

[43]  N. Thornberry,et al.  Caspases: killer proteases. , 1997, Trends in biochemical sciences.

[44]  N. Thornberry,et al.  A Combinatorial Approach Defines Specificities of Members of the Caspase Family and Granzyme B , 1997, The Journal of Biological Chemistry.

[45]  Guy S. Salvesen,et al.  X-linked IAP is a direct inhibitor of cell-death proteases , 1997, Nature.

[46]  J. Coligan,et al.  Casein kinase II is a selective target of HIV-1 transcriptional inhibitors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[47]  P. Bucher,et al.  The CARD domain: a new apoptotic signalling motif. , 1997, Trends in biochemical sciences.

[48]  K. Bauer,et al.  Activation of apoptosis by Apo-2 ligand is independent of FADD but blocked by CrmA , 1996, Current Biology.

[49]  S. Marsters,et al.  Induction of Apoptosis by Apo-2 Ligand, a New Member of the Tumor Necrosis Factor Cytokine Family* , 1996, The Journal of Biological Chemistry.

[50]  K. Tamai,et al.  Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes , 1996, Nature.

[51]  C A Smith,et al.  Identification and characterization of a new member of the TNF family that induces apoptosis. , 1995, Immunity.

[52]  C. Allende,et al.  Protein kinase CK2: an enzyme with multiple substrates and a puzzling regulation , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  R. Firtel,et al.  Molecular cloning of casein kinase II alpha subunit from Dictyostelium discoideum and its expression in the life cycle , 1992, Molecular and cellular biology.

[54]  R. Padmanabha,et al.  Isolation, sequencing, and disruption of the yeast CKA2 gene: casein kinase II is essential for viability in Saccharomyces cerevisiae , 1990, Molecular and cellular biology.

[55]  O. Issinger,et al.  Casein kinase II is elevated in solid human tumours and rapidly proliferating non-neoplastic tissue. , 1990, European journal of biochemistry.

[56]  R. Zandomeni.  Kinetics of inhibition by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole on calf thymus casein kinase II. , 1989, The Biochemical journal.

[57]  D. Litchfield.  Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. , 2003, The Biochemical journal.

[58]  G. Gores,et al.  Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. , 1999, The Journal of clinical investigation.