Advertisement

Medical Oncology

, 30:757 | Cite as

Protein kinase C (PKC) as a drug target in chronic lymphocytic leukemia

  • Julhash U. KaziEmail author
  • Nuzhat N. Kabir
  • Lars Rönnstrand
Review Article

Abstract

Protein kinase C (PKC) belongs to a family of ten serine/threonine protein kinases encoded by nine genes. This family of proteins plays critical roles in signal transduction which results in cell proliferation, survival, differentiation and apoptosis. Due to differential subcellular localization and tissue distribution, each member displays distinct signaling characteristics. In this review, we have summarized the roles of PKC family members in chronic lymphocytic leukemia (CLL). CLL is a heterogeneous hematological disorder with survival ranging from months to decades. PKC isoforms are differentially expressed in CLL and play critical roles in CLL pathogenesis. Thus, isoform-specific PKC inhibitors may be an attractive option for CLL treatment.

Keywords

CLL B-CLL FLT3 KIT PDGFR CSF1R M-CSFR 

Notes

Acknowledgments

We thank Professor Christer Larsson at Lund University for comments on manuscript. This research was funded by the Swedish Cancer Society, the Swedish Children’s Cancer Organization, the Swedish Research Council, Stiftelsen Olle Engkvist Byggmästare, Ollie Elof Ericssons Stiftelse, Stiftelsen Lars Hiertas Minne, Royal Physiographical Society and ALF governmental clinical grant.

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    Kabir NN, Kazi JU. Comparative analysis of human and bovine protein kinases reveals unique relationship and functional diversity. Genet Mol Biol. 2011;34(4):587–91. doi: 10.1590/S1415-47572011005000035.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Kazi JU, Kabir NN, Soh JW. Bioinformatic prediction and analysis of eukaryotic protein kinases in the rat genome. Gene. 2008;410(1):147–53. doi: 10.1016/j.gene.2007.12.003.CrossRefPubMedGoogle Scholar
  3. 3.
    Inoue M, Kishimoto A, Takai Y, Nishizuka Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain. J Biol Chem. 1977;252(21):7610–6.PubMedGoogle Scholar
  4. 4.
    Kazi JU. The mechanism of protein kinase C regulation. Frontiers Biol. 2011;6(4):328–36. doi: 10.1007/s11515-011-1070-5.Google Scholar
  5. 5.
    Kazi JU, Soh JW. Role of regulatory domain mutants of PKC isoforms in c-fos induction. Bull Korean Chem Soc. 2008;29(1):252–4.CrossRefGoogle Scholar
  6. 6.
    Kazi JU, Soh JW. Induction of the nuclear proto-oncogene c-fos by the phorbol ester TPA and v-H-Ras. Mol Cells. 2008;26(5):462–7.PubMedGoogle Scholar
  7. 7.
    Rodriguez-Vicente AE, Diaz MG, Hernandez-Rivas JM. Chronic lymphocytic leukemia: a clinical and molecular heterogenous disease. Cancer Genet. 2013;206(3):49–62. doi: 10.1016/j.cancergen.2013.01.003.CrossRefPubMedGoogle Scholar
  8. 8.
    Steinberg SF. Structural basis of protein kinase C isoform function. Physiol Rev. 2008;88(4):1341–78. doi: 10.1152/physrev.00034.2007.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Benes CH, Wu N, Elia AE, Dharia T, Cantley LC, Soltoff SP. The C2 domain of PKCdelta is a phosphotyrosine binding domain. Cell. 2005;121(2):271–80. doi: 10.1016/j.cell.2005.02.019.CrossRefPubMedGoogle Scholar
  10. 10.
    Kazi JU, Kim CR, Soh JW. Subcellular localization of diacylglycerol-responsive protein kinase C isoforms in HeLa cells. Bull Korean Chem Soc. 2009;30(9):1981–4.CrossRefGoogle Scholar
  11. 11.
    Kazi JU, Soh JW. Isoform-specific translocation of PKC isoforms in NIH3T3 cells by TPA. Biochem Biophys Res Commun. 2007;364(2):231–7. doi: 10.1016/j.bbrc.2007.09.123.CrossRefPubMedGoogle Scholar
  12. 12.
    Hocevar BA, Fields AP. Selective translocation of beta II-protein kinase C to the nucleus of human promyelocytic (HL60) leukemia cells. J Biol Chem. 1991;266(1):28–33.PubMedGoogle Scholar
  13. 13.
    Sakai N, Sasaki K, Ikegaki N, Shirai Y, Ono Y, Saito N. Direct visualization of the translocation of the gamma-subspecies of protein kinase C in living cells using fusion proteins with green fluorescent protein. J Cell Biol. 1997;139(6):1465–76.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Looby E, Long A, Kelleher D, Volkov Y. Bile acid deoxycholate induces differential subcellular localisation of the PKC isoenzymes beta 1, epsilon and delta in colonic epithelial cells in a sodium butyrate insensitive manner. Int J Cancer. 2005;114(6):887–95. doi: 10.1002/ijc.20803.CrossRefPubMedGoogle Scholar
  15. 15.
    Goodnight JA, Mischak H, Kolch W, Mushinski JF. Immunocytochemical localization of eight protein kinase C isozymes overexpressed in NIH 3T3 fibroblasts. Isoform-specific association with microfilaments, Golgi, endoplasmic reticulum, and nuclear and cell membranes. J Biol Chem. 1995;270(17):9991–10001.CrossRefPubMedGoogle Scholar
  16. 16.
    Redig AJ, Platanias LC. The protein kinase C (PKC) family of proteins in cytokine signaling in hematopoiesis. J Interferon Cytokine Res. 2007;27(8):623–36. doi: 10.1089/jir2007.0007.CrossRefPubMedGoogle Scholar
  17. 17.
    Koivunen J, Aaltonen V, Peltonen J. Protein kinase C (PKC) family in cancer progression. Cancer Lett. 2006;235(1):1–10. doi: 10.1016/j.canlet.2005.03.033.CrossRefPubMedGoogle Scholar
  18. 18.
    Leirdal M, Sioud M. Ribozyme inhibition of the protein kinase C alpha triggers apoptosis in glioma cells. Br J Cancer. 1999;80(10):1558–64. doi: 10.1038/sj.bjc.6690560.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Detjen KM, Brembeck FH, Welzel M, Kaiser A, Haller H, Wiedenmann B, Rosewicz S. Activation of protein kinase Calpha inhibits growth of pancreatic cancer cells via p21(cip)-mediated G(1) arrest. J Cell Sci. 2000;113(17):3025–35.PubMedGoogle Scholar
  20. 20.
    Scaglione-Sewell B, Abraham C, Bissonnette M, Skarosi SF, Hart J, Davidson NO, Wali RK, Davis BH, Sitrin M, Brasitus TA. Decreased PKC-alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells. Cancer Res. 1998;58(5):1074–81.PubMedGoogle Scholar
  21. 21.
    Kabir NN, Rönnstrand L, Kazi JU. Protein kinase C expression is deregulated in chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(10):2288–90. doi: 10.3109/10428194.2013.769220.CrossRefPubMedGoogle Scholar
  22. 22.
    Marengo B, De Ciucis C, Ricciarelli R, Pronzato MA, Marinari UM, Domenicotti C. Protein kinase C: an attractive target for cancer therapy. Cancers. 2011;3(1):531–67. doi: 10.3390/cancers3010531.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Zum Buschenfelde CM, Wagner M, Lutzny G, Oelsner M, Feuerstacke Y, Decker T, Bogner C, Peschel C, Ringshausen I. Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70. Leukemia. 2010;24(1):141–52. doi: 10.1038/leu.2009.216.CrossRefPubMedGoogle Scholar
  24. 24.
    Ringshausen I, Schneller F, Bogner C, Hipp S, Duyster J, Peschel C, Decker T. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood. 2002;100(10):3741–8. doi: 10.1182/blood-2002-02-0539.CrossRefPubMedGoogle Scholar
  25. 25.
    Alvaro V, Levy L, Dubray C, Roche A, Peillon F, Querat B, Joubert D. Invasive human pituitary tumors express a point-mutated alpha-protein kinase-C. J Clin Endocrinol Metab. 1993;77(5):1125–9.PubMedGoogle Scholar
  26. 26.
    Prevostel C, Martin A, Alvaro V, Jaffiol C, Joubert D. Protein kinase C alpha and tumorigenesis of the endocrine gland. Horm Res. 1997;47(4–6):140–4.PubMedGoogle Scholar
  27. 27.
    Vallentin A, Lo TC, Joubert D. A single point mutation in the V3 region affects protein kinase Calpha targeting and accumulation at cell–cell contacts. Mol Cell Biol. 2001;21(10):3351–63. doi: 10.1128/MCB.21.10.3351-3363.2001.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Zhu Y, Dong Q, Tan BJ, Lim WG, Zhou S, Duan W. The PKCalpha-D294G mutant found in pituitary and thyroid tumors fails to transduce extracellular signals. Cancer Res. 2005;65(11):4520–4. doi: 10.1158/0008-5472.CAN-04-4506.CrossRefPubMedGoogle Scholar
  29. 29.
    Siller G, Rosen R, Freeman M, Welburn P, Katsamas J, Ogbourne SM. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: results of a randomized phase IIa trial. Australas J Dermatol. 2010;51(2):99–105. doi: 10.1111/j.1440-0960.2010.00626.x.CrossRefPubMedGoogle Scholar
  30. 30.
    Kedei N, Lundberg DJ, Toth A, Welburn P, Garfield SH, Blumberg PM. Characterization of the interaction of ingenol 3-angelate with protein kinase C. Cancer Res. 2004;64(9):3243–55.CrossRefPubMedGoogle Scholar
  31. 31.
    Lee WY, Hampson P, Coulthard L, Ali F, Salmon M, Lord JM, Scheel-Toellner D. Novel antileukemic compound ingenol 3-angelate inhibits T cell apoptosis by activating protein kinase Ctheta. J Biol Chem. 2010;285(31):23889–98. doi: 10.1074/jbc.M109.041962.CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Kazi JU, Rönnstrand L. Src-Like adaptor protein (SLAP) binds to the receptor tyrosine kinase Flt3 and modulates receptor stability and downstream signaling. PLoS ONE. 2012;7(12):e53509. doi: 10.1371/journal.pone.0053509.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Kazi JU, Sun J, Phung B, Zadjali F, Flores-Morales A, Rönnstrand L. Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. J Biol Chem. 2012;287(43):36509–17. doi: 10.1074/jbc.M112.376111.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Lin DC, Yin T, Koren-Michowitz M, Ding LW, Gueller S, Gery S, Tabayashi T, Bergholz U, Kazi JU, Rönnstrand L, Stocking C, Koeffler HP. Adaptor protein Lnk binds to and inhibits normal and leukemic FLT3. Blood. 2012;120(16):3310–7. doi: 10.1182/blood-2011-10-388611.CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Kazi JU, Rönnstrand L. Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling. Mol Oncol. 2013;7(3):693–703. doi: 10.1016/j.molonc.2013.02.020.CrossRefPubMedGoogle Scholar
  36. 36.
    Kazi JU, Rönnstrand L. FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia. Mol Oncol. 2013;7(3):402–18. doi: 10.1016/j.molonc.2012.11.003.CrossRefPubMedGoogle Scholar
  37. 37.
    Kazi JU, Vaapil M, Agarwal S, Bracco E, Pahlman S, Rönnstrand L. The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling. Cell Signal. 2013;25(9):1852–60. doi: 10.1016/j.cellsig.2013.05.016.CrossRefPubMedGoogle Scholar
  38. 38.
    Heiss E, Masson K, Sundberg C, Pedersen M, Sun J, Bengtsson S, Rönnstrand L. Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood. 2006;108(5):1542–50. doi: 10.1182/blood-2005-07-008896.CrossRefPubMedGoogle Scholar
  39. 39.
    Kabir NN, Rönnstrand L, Kazi JU. Deregulation of protein phosphatase expression in acute myeloid leukemia. Med Oncol. 2013;30(2):517. doi: 10.1007/s12032-013-0517-8.CrossRefPubMedGoogle Scholar
  40. 40.
    Alimandi M, Heidaran MA, Gutkind JS, Zhang J, Ellmore N, Valius M, Kazlauskas A, Pierce JH, Li W. PLC-gamma activation is required for PDGF-betaR-mediated mitogenesis and monocytic differentiation of myeloid progenitor cells. Oncogene. 1997;15(5):585–93. doi: 10.1038/sj.onc.1201221.CrossRefPubMedGoogle Scholar
  41. 41.
    Salhany KE, Robinson-Benion C, Candia AF, Pledger WJ, Holt JT. Differential induction of the c-fos promoter through distinct PDGF receptor-mediated signaling pathways. J Cell Physiol. 1992;150(2):386–95. doi: 10.1002/jcp.1041500223.CrossRefPubMedGoogle Scholar
  42. 42.
    Choudhury GG, Biswas P, Grandaliano G, Abboud HE. Involvement of PKC-alpha in PDGF-mediated mitogenic signaling in human mesangial cells. Am J Physiol. 1993;265(5 Pt 2):F634–42.PubMedGoogle Scholar
  43. 43.
    Neri LM, Billi AM, Manzoli L, Rubbini S, Gilmour RS, Cocco L, Martelli AM. Selective nuclear translocation of protein kinase C alpha in Swiss 3T3 cells treated with IGF-I PDGF and EGF. FEBS lett. 1994;347(1):63–8.CrossRefPubMedGoogle Scholar
  44. 44.
    Leng L, Du B, Consigli S, McCaffrey TA. Translocation of protein kinase C-delta by PDGF in cultured vascular smooth muscle cells: inhibition by TGF-beta 1. Artery. 1996;22(3):140–54.PubMedGoogle Scholar
  45. 45.
    Blume-Jensen P, Siegbahn A, Stabel S, Heldin CH, Rönnstrand L. Increased Kit/SCF receptor induced mitogenicity but abolished cell motility after inhibition of protein kinase C. EMBO J. 1993;12(11):4199–209.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Kozawa O, Blume-Jensen P, Heldin CH, Rönnstrand L. Involvement of phosphatidylinositol 3′-kinase in stem-cell-factor-induced phospholipase D activation and arachidonic acid release. Eur J Biochem/FEBS. 1997;248(1):149–55.CrossRefGoogle Scholar
  47. 47.
    Wang Y, Mo X, Piper MG, Wang H, Parinandi NL, Guttridge D, Marsh CB. M-CSF induces monocyte survival by activating NF-kappaB p65 phosphorylation at Ser276 via protein kinase C. PLoS One. 2011;6(12):e28081. doi: 10.1371/journal.pone.0028081.CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Lee AW. The role of atypical protein kinase C in CSF-1-dependent Erk activation and proliferation in myeloid progenitors and macrophages. PLoS One. 2011;6(10):e25580. doi: 10.1371/journal.pone.0025580.CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Kabir NN, Rönnstrand L, Kazi JU. FLT3 mutations in patients with childhood acute lymphoblastic leukemia (ALL). Med Oncol. 2013;30(1):462. doi: 10.1007/s12032-013-0462-6.CrossRefPubMedGoogle Scholar
  50. 50.
    Dosil M, Wang S, Lemischka IR. Mitogenic signalling and substrate specificity of the Flk2/Flt3 receptor tyrosine kinase in fibroblasts and interleukin 3-dependent hematopoietic cells. Mol Cell Biol. 1993;13(10):6572–85.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Arora D, Stopp S, Bohmer SA, Schons J, Godfrey R, Masson K, Razumovskaya E, Rönnstrand L, Tanzer S, Bauer R, Bohmer FD, Muller JP. Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. J Biol Chem. 2011;286(13):10918–29. doi: 10.1074/jbc.M110.205021.CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Barragan M, de Frias M, Iglesias-Serret D, Campas C, Castano E, Santidrian AF, Coll-Mulet L, Cosialls AM, Domingo A, Pons G, Gil J. Regulation of Akt/PKB by phosphatidylinositol 3-kinase-dependent and -independent pathways in B-cell chronic lymphocytic leukemia cells: role of protein kinase C{beta}. J Leukoc Biol. 2006;80(6):1473–9. doi: 10.1189/jlb.0106041.CrossRefPubMedGoogle Scholar
  53. 53.
    Komada F, Nishikawa M, Uemura Y, Morita K, Hidaka H, Shirakawa S. Expression of three major protein kinase C isozymes in various types of human leukemic cells. Cancer Res. 1991;51(16):4271–8.PubMedGoogle Scholar
  54. 54.
    Alkan S, Huang Q, Ergin M, Denning MF, Nand S, Maududi T, Paner GP, Ozpuyan F, Izban KF. Survival role of protein kinase C (PKC) in chronic lymphocytic leukemia and determination of isoform expression pattern and genes altered by PKC inhibition. Am J Hematol. 2005;79(2):97–106. doi: 10.1002/ajh.20352.CrossRefPubMedGoogle Scholar
  55. 55.
    Abrams ST, Lakum T, Lin K, Jones GM, Treweeke AT, Farahani M, Hughes M, Zuzel M, Slupsky JR. B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CbetaII. Blood. 2007;109(3):1193–201. doi: 10.1182/blood-2006-03-012021.CrossRefPubMedGoogle Scholar
  56. 56.
    Klein U, Dalla-Favera R. New insights into the phenotype and cell derivation of B cell chronic lymphocytic leukemia. Curr Top Microbiol Immunol. 2005;294:31–49.PubMedGoogle Scholar
  57. 57.
    Hans CP, Weisenburger DD, Greiner TC, Chan WC, Aoun P, Cochran GT, Pan Z, Smith LM, Lynch JC, Bociek RG, Bierman PJ, Vose JM, Armitage JO. Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Mod Pathol. 2005;18(10):1377–84. doi: 10.1038/modpathol.3800434.CrossRefPubMedGoogle Scholar
  58. 58.
    Espinosa I, Briones J, Bordes R, Brunet S, Martino R, Sureda A, Prat J, Sierra J. Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma. Ann Hematol. 2006;85(9):597–603. doi: 10.1007/s00277-006-0144-y.CrossRefPubMedGoogle Scholar
  59. 59.
    Gokmen-Polar Y, Murray NR, Velasco MA, Gatalica Z, Fields AP. Elevated protein kinase C betaII is an early promotive event in colon carcinogenesis. Cancer Res. 2001;61(4):1375–81.PubMedGoogle Scholar
  60. 60.
    Murray NR, Davidson LA, Chapkin RS, Clay Gustafson W, Schattenberg DG, Fields AP. Overexpression of protein kinase C betaII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis. J Cell Biol. 1999;145(4):699–711.CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005;352(8):804–15. doi: 10.1056/NEJMra041720.CrossRefPubMedGoogle Scholar
  62. 62.
    Oellerich T, Bremes V, Neumann K, Bohnenberger H, Dittmann K, Hsiao HH, Engelke M, Schnyder T, Batista FD, Urlaub H, Wienands J. The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85. EMBO J. 2011;30(17):3620–34. doi: 10.1038/emboj.2011.251.CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Shinohara H, Yasuda T, Aiba Y, Sanjo H, Hamadate M, Watarai H, Sakurai H, Kurosaki T. PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J Exp Med. 2005;202(10):1423–31. doi: 10.1084/jem.20051591.CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    Kang SW, Wahl MI, Chu J, Kitaura J, Kawakami Y, Kato RM, Tabuchi R, Tarakhovsky A, Kawakami T, Turck CW, Witte ON, Rawlings DJ. PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization. EMBO J. 2001;20(20):5692–702. doi: 10.1093/emboj/20.20.5692.CrossRefPubMedCentralPubMedGoogle Scholar
  65. 65.
    Abrams ST, Brown BR, Zuzel M, Slupsky JR. Vascular endothelial growth factor stimulates protein kinase CbetaII expression in chronic lymphocytic leukemia cells. Blood. 2010;115(22):4447–54. doi: 10.1182/blood-2009-06-229872.CrossRefPubMedGoogle Scholar
  66. 66.
    Chen L, Widhopf G, Huynh L, Rassenti L, Rai KR, Weiss A, Kipps TJ. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2002;100(13):4609–14. doi: 10.1182/blood-2002-06-1683.CrossRefPubMedGoogle Scholar
  67. 67.
    Chen L, Huynh L, Apgar J, Tang L, Rassenti L, Weiss A, Kipps TJ. ZAP-70 enhances IgM signaling independent of its kinase activity in chronic lymphocytic leukemia. Blood. 2008;111(5):2685–92. doi: 10.1182/blood-2006-12-062265.CrossRefPubMedCentralPubMedGoogle Scholar
  68. 68.
    Gobessi S, Laurenti L, Longo PG, Sica S, Leone G, Efremov DG. ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells. Blood. 2007;109(5):2032–9. doi: 10.1182/blood-2006-03-011759.CrossRefPubMedGoogle Scholar
  69. 69.
    Lutzny G, Kocher T, Schmidt-Supprian M, Rudelius M, Klein-Hitpass L, Finch AJ, Durig J, Wagner M, Haferlach C, Kohlmann A, Schnittger S, Seifert M, Wanninger S, Zaborsky N, Oostendorp R, Ruland J, Leitges M, Kuhnt T, Schafer Y, Lampl B, Peschel C, Egle A, Ringshausen I. Protein kinase c-beta-dependent activation of NF-kappaB in stromal cells is indispensable for the survival of chronic lymphocytic leukemia B cells in vivo. Cancer Cell. 2013;23(1):77–92. doi: 10.1016/j.ccr.2012.12.003.CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    Kabir NN, Kazi JU. Selective mutation in ATP-binding site reduces affinity of drug to the kinase: a possible mechanism of chemo-resistance. Med Oncol. 2013;30(1):448. doi: 10.1007/s12032-012-0448-9.CrossRefPubMedGoogle Scholar
  71. 71.
    Mochly-Rosen D, Das K, Grimes KV. Protein kinase C, an elusive therapeutic target? Nat Rev Drug Discov. 2012;11(12):937–57. doi: 10.1038/nrd3871.CrossRefPubMedCentralPubMedGoogle Scholar
  72. 72.
    Ganeshaguru K, Wickremasinghe RG, Jones DT, Gordon M, Hart SM, Virchis AE, Prentice HG, Hoffbrand AV, Man A, Champain K, Csermak K, Mehta AB. Actions of the selective protein kinase C inhibitor PKC412 on B-chronic lymphocytic leukemia cells in vitro. Haematologica. 2002;87(2):167–76.PubMedGoogle Scholar
  73. 73.
    Byrd JC, Shinn C, Willis CR, Flinn IW, Lehman T, Sausville E, Lucas D, Grever MR. UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism. Exp Hematol. 2001;29(6):703–8.CrossRefPubMedGoogle Scholar
  74. 74.
    Barragan M, Bellosillo B, Campas C, Colomer D, Pons G, Gil J. Involvement of protein kinase C and phosphatidylinositol 3-kinase pathways in the survival of B-cell chronic lymphocytic leukemia cells. Blood. 2002;99(8):2969–76.CrossRefPubMedGoogle Scholar
  75. 75.
    Lahn M, Sundell K, Moore S. Targeting protein kinase C-alpha (PKC-alpha) in cancer with the phosphorothioate antisense oligonucleotide aprinocarsen. Ann N Y Acad Sci. 2003;1002:263–70.CrossRefPubMedGoogle Scholar
  76. 76.
    Ringshausen I, Oelsner M, Weick K, Bogner C, Peschel C, Decker T. Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL. Leukemia. 2006;20(3):514–20. doi: 10.1038/sj.leu.2404113.CrossRefPubMedGoogle Scholar
  77. 77.
    Best OG, Tam C. Protein Kinase C isoform expression in chronic lymphocytic leukemia: a potential target for therapy? Leuk Lymphoma. 2013;54(10):2098–9. doi: 10.3109/10428194.2013.779692.CrossRefPubMedGoogle Scholar
  78. 78.
    Virchis A, Ganeshaguru K, Hart S, Jones D, Fletcher L, Wright F, Wickremasinghe R, Man A, Csermak K, Meyer T, Fabbro D, Champain K, Yap A, Prentice HG, Mehta A. A novel treatment approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C. Hematol J. 2002;3(3):131–6. doi: 10.1038/sj.thj.6200165.CrossRefPubMedGoogle Scholar
  79. 79.
    Chen YB, LaCasce AS. Enzastaurin. Expert Opin Investig Drugs. 2008;17(6):939–44. doi: 10.1517/13543784.17.6.939.CrossRefPubMedGoogle Scholar
  80. 80.
    Ysebaert L, Morschhauser F. Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies. Expert Opin Investig Drugs. 2011;20(8):1167–74. doi: 10.1517/13543784.2011.590130.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Julhash U. Kazi
    • 1
    • 2
    Email author
  • Nuzhat N. Kabir
    • 2
  • Lars Rönnstrand
    • 1
  1. 1.Translational Cancer ResearchLund UniversityLundSweden
  2. 2.Laboratory of Computational BiochemistryKN Biomedical Research InstituteBarisalBangladesh

Personalised recommendations