Cancer Letters
Volume 206, Issue 2 , Pages 137-148 , 8 April 2004

From Ras signalling to ChoK inhibitors: a further advance in anticancer drug design

Received 21 July 2003 ,Accepted 1 August 2003.

References 

  1. Ferlay J, Bray F, Pisani P, Parkin DM. Cancer Incidence, Mortality and Prevalence Worldwide. IARC Cancer Base. 5. Lyon: IARC Press; 2001;
  2. Aznar S, Lacal JC. Rho signals to cell growth and apoptosis. Cancer Lett. 2001;165:1–10
  3. Ramirez-De Molina A, Rodriguez-Gonzalez A, Lacal JC. Targeting new anticancer drugs within signalling pathways regulated by the Ras GTPase superfamily. Int. J. Oncol. 2001;19:5–17
  4. Malumbres M, Pellicer A. RAS pathways to cell cycle control and cell transformation. Front Biosci. 1998;3:887–912
  5. Van Aelst L, D'Souza-Schorey C. RhoGTPases and signaling networks. Genes Dev. 1997;11:2295–2322
  6. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–4689
  7. Rodenhuis S. ras and human tumors. Semin. Cancer Biol. 1992;3:241–247
  8. Crespo P, Leon J. Ras proteins in the control of the cell cycle and cell differentiation. Cell. Mol. Life Sci. 2000;57:1613–1636
  9. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53:549–554
  10. Smit VTH, Boot AJM, Smits AMM, Fleuren GJ, Cornelisse CJ, Bos JL. K-ras codon 12 point mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acid Res. 1988;16:7773–7782
  11. Halter SA, Webb L, Rose J. Lack of ras mutations and prediction of long-term survival in carcinoma of the colon. Mod. Pathol. 1992;5:131–134
  12. Breivik J, Meling GI, Spurkland A, Rognum TO, Gaudernack G. K-ras mutation in colorectal cancer: relations to patient age, sex and tumour location. Br. J. Cancer. 1994;69:367–371
  13. Baba I, Shirasawa S, Iwamoto R, Okumura K, Tsunoda T, Nishioka M, et al.  Involvement of deregulated epiregulin expression in tumorigenesis in vivo through activated Ki-Ras signaling pathway in human colon cancer cells. Cancer Res. 2000;60:6886–6889
  14. Rodenhuis S, Slebos RJ. Clinical significance of ras oncogene activation in human lung cancer. Cancer Res. 1992;52:2665s–2669s
  15. Kiaris H, Spandidos D. Int. J. Oncol. 1995;7:413–421
  16. Meuwissen R, Linn SC, van der Valk M, Mooi WJ, Berns A. Mouse model for lung tumorigenesis through Cre/lox controlled sporadic activation of the K-Ras oncogene. Oncogene. 2001;20:6551–6558
  17. Zhang Z, Wang Y, Vikis HG, Johnson L, Liu G, Li J, et al.  Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat. Genet. 2001;29:25–33
  18. Shinohara N, Koyanagi T. Ras signal transduction in carcinogenesis and progression of bladder cancer: molecular target for treatment?. Urol. Res. 2002;30:273–281
  19. Konishi N, Hiasa Y, Tsuzuki T, Tao M, Enomoto T, Miller GJ. Comparison of ras activation in prostate carcinoma in Japanese and American men. Prostate. 1997;30:53–57
  20. Shiraishi T, Muneyuki T, Fukutome K, Ito H, Kotake T, Watanabe M, et al. Mutations of ras genes are relatively frequent in Japanese prostate cancers: pointing to genetic differences between populations. Anticancer Res. 1998;18:2789–2792
  21. Spandidos DA, Liloglou T, Arvanitis D, Gourtsoyiannis NC. Ras gene activation in human small intestinal tumors. Int. J. Oncol. 1993;2:513–518
  22. Asamoto M, Toriyama-Baba H, Ohnishi T, Naito A, Ota T, Ando A, et al.  Transgenic Rats Carrying Human c-Ha-ras Proto-oncogene Are Highly Susceptible to N-Nitrosomethylbenzylamine Induction of Esophageal Tumorigenesis. Jpn. J. Cancer Res. 2002;93:744–751
  23. Watanabe T, Kashida Y, Yasuhara K, Koujitani T, Hirose M, Mitsumori K. Rapid induction of uterine endometrial proliferative lesions in transgenic mice carrying a human prototype c-Ha-ras gene (rasH2 mice) given a single intraperitoneal injection of N-ethyl-N-nitrosourea. Cancer Lett. 2002;188:39–46
  24. Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc. Natl. Acad. Sci. USA. 1988;85:1629–1633
  25. Toksoz D, Farr CJ, Marshall CJ. ras gene activation in a minor proportion of the blast population in acute myeloid leukaemia. Oncogene. 1987;1:9–13
  26. Kraus MH, Yuasa Y, Aaronson SA. A position 12-activated H-ras oncogene in all HS578T mammary carcinosarcoma cells but not normal mammary cells of the same patient. Proc. Natl. Acad. Sci. USA. 1984;81:5384–5388
  27. Spandidos DA. Oncogene activation in malignant transformation: a study of H-ras in human breast cancer. Anticancer Res. 1987;7:991–996
  28. Malaney S, Daly RJ. The ras signaling pathway in mammary tumorigenesis and metastasis. J. Mammary Gland Biol. Neoplasia. 2001;6:101–113
  29. D'Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, et al.  c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat. Med. 2001;7:235–239
  30. Hulit J, Di Vizio D, Pestell RG. Inducible transgenics. New lessons on events governing the induction and commitment in mammary tumorigenesis. Breast Cancer Res. 2001;3:209–212
  31. Janda E, Litos G, Grunert S, Downward J, Beug H. Oncogenic Ras/Her-2 mediate hyperproliferation of polarized epithelial cells in 3D cultures and rapid tumor growth via the PI3K pathway. Oncogene. 2002;21:5148–5159
  32. Ryo A, Liou YC, Wulf G, Nakamura M, Lee SW, Lu KP. PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol. Cell Biol. 2002;22:5281–5295
  33. Lazarov M, Kubo Y, Cai T, Dajee M, Tarutani M, Lin Q, et al.  CDK4 coexpression with Ras generates malignant human epidermal tumorigenesis. Nat. Med. 2002;8:1105–1114
  34. Kerkhoff E, Rapp UR. Induction of cell proliferation in quiescent NIH 3T3 cells by oncogenic c-Raf-1. Mol. Cell Biol. 1997;17:2576–2586
  35. Friedman M, Tikoo A, Varg M, Murphy A, Nur-E-Kama MS, Maruta H. The minimal fragments of c-Raf-1 and NF1 that can suppress v-Ha-Ras-induced malignant phenotype. J. Biol. Chem. 1994;269:30105–30108
  36. Kerkhoff E, Fedorov LM, Siefken R, Walter AO, Papadopoulos T, Rapp UR. Lung-targeted expression of the c-Raf-1 kinase in transgenic mice exposes a novel oncogenic character of the wild-typeprotein. Cell Growth Differ. 2000;11:185–190
  37. Janda E, Lehmann K, Killisch I, Jechlinger M, Herzig M, Downward J, et al. Ras and TGF(beta) cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J. Cell Biol. 2002;156:299–313
  38. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418:934
  39. Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, et al.  Distintc requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 2002;16:2045–2057
  40. Urano T, Emky R, Feig LA. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. Eur. Mol. Biol. Org. J. 1996;15:810–816
  41. White MA, Vale T, Camonis JH, Schaefer E, Wigle MH. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J. Biol. Chem. 1996;271:16439–16442
  42. Okazaki M, Kishida S, Murai H, Hinoi T, Kikuchi A. Ras-interacting domain of Ral GDP dissociation stimulator like (RGL) reverses v-Ras-induced transformation and Raf-1 activation in NIH3T3. Cancer Res. 1996;56:2387–2392
  43. Bos JL. Ras-like GTPases. Biochim. Biophys. Acta. 1997;1333:19–31
  44. Senga T, Iwamoto T, Kitamura T, Miyake Y, Hamaguchi M. JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells. J. Biol. Chem. 2001;276:32678–32681
  45. Tian X, Rusanescu G, Hou W, Schaffhausen B, Feig LA. PDK1 mediates growth factor-induced Ral-GEF activation by a kinase-independent mechanism. Eur. Mol. Biol. Org. J. 2002;21:1327–1338
  46. Ward Y, Wang W, Woodhouse E, Linnoila I, Liotta L, Kelly K. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Mol. Cell Biol. 2001;21:5958–5969
  47. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–1657
  48. Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, et al. PKB participates in GLUT4 translocation by insulin in L6 myoblasts. Mol. Cell Biol. 1999;19:4008–4018
  49. Shaw M, Chen P. Role of PKB and MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells. Fed. Eur. Biochem. Soc. Lett. 1999;461:120–124
  50. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dethar S. Phosphoinositide 3-kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/Akt by the integrin linked Kinase. Proc. Natl. Acad. Sci. USA. 1998;95:11211–11216
  51. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–1657
  52. Romashkova JA, Makarov SS. NF-kappB is a target of Akt in anti-apoptotic PDGF signalling. Nature. 1999;401:86–90
  53. Sabbatini P, McCormick F. Phosphoinositide-OH Kinase (PI3K) and PKB/Akt delay the onset of p53-mediated, transcriptionally dependent apoptosis. J. Biol. Chem. 1999;274:24263–24269
  54. Khwaja A. Akt is more than just a bad kinase. Nature. 1999;401:33–34
  55. Hawkins PT, Eguinoa A, Qui RG, Stokoe D, Cooke T, Walters R, et al  PDGF an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr. Biol. 1995;5:393–403
  56. Van Weering DH, de Rooij J, Marte B, Downward JL, Bos BM. Protein Kinase B activation and lamellipodium formation are independent phosphoinositide 3-kinase-mediated events differentially regulated by endogenous Ras. Mol. Cell Biol. 1998;18:1802–1811
  57. Moscatello DK, Holgado-Madruga M, Emlet DR, Montgomery RB, Wong AJ. Constitutive activation of phosphatidylinositol 3-kinase by a naturally occurring mutant epidermal growth factorreceptor. J. Biol. Chem. 1998;273:200–206
  58. Hu L, Zaloudek C, Mills GE, Gray J, Jaffe RB. In vivo and in vitro ovarian carcinoma growth inhibition by a phosphoatydilinositol 3-kinase inhibitor (LY294002). Clin. Cancer Res. 2000;6:880–886
  59. Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, et al.  PIK3CA as an oncogene in cervical cancer. Oncogene. 2000;19:2739–2744
  60. Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalo-Garcia A, Leonardo E, Wennstrom S, et al.  Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. Eur. Mol. Biol. Org. J. 1998;17:743–753
  61. Barbadelli A, Basile ML, Audero E, Giordano S, Wennstromn S, Menard S, et al.  Concomitant activation of pathways downstream of Grb2 and PI 3-kinase is required for MET-mediated metastasis. Oncogene. 1999;18:1139–1146
  62. Jiang BH, Zheng JZ, Aoki M, Vogt PK. Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc. Natl. Acad. Sci. USA. 2000;97:1749–1753
  63. Mayo LD, Donner RB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem. Sci. 2002;27:462–467
  64. Siebert R, Gesk S, Harder S, Plotz S, Matthiesen P, et al.  Deletions in the long arm of chromosome 10 in lymphomas with t(14;18): a pathogenetic role of the tumor supressor genes PTEN/MMAC1 and MXI1?. Blood. 1998;92:4487–4489
  65. Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al.  The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc. Natl. Acad. Sci. USA. 1998;95:13513–13518
  66. Kloog Y, Cox AD, Sinensky M. Concepts in Ras-directed therapy. Expert Opin. Investig. Drugs. 1999;8:2121–2140
  67. Sebolt-Leopold JS. Development of anticancer drugs targeting the MAP kinase pathway. Oncogene. 2000;19:6594–6599
  68. Johnston SR. Farnesyl transferase inhibitors: a novel targeted therapy for cancer. Lancet Oncol. 2001;2:18–26
  69. Prendergast GC. Actin' up: RhoB in cancer and apoptosis. Nat. Rev. Cancer. 2001;1:162–168
  70. Haluska P, Dy GK, Adjei AA. Farnesyl transferase inhibitors as anticancer agents. Eur. J. Cancer. 2002;38:1685–1700
  71. Lerner EC, Zhang TT, Knowles DB, Qian Y, Hamilton AD, Sebti SM. Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene. 1997;15:1283–1288
  72. Manges R, Corral T, Kohl NE, Symmans WF, Lu S, Malumberes M, et al.  Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res. 1998;58:1253–1259
  73. Hernandez-Alcoceba R, Saniger L, Campos J, Nuñez MC, Khaless F, Gallo MA, et al.  Choline Kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene. 1997;15:2289–2301
  74. Hernandez-Alcoceba R, Fernandez F, Lacal JC. In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery. Cancer Res. 1999;59:3112–3118
  75. Ramirez de Molina A, Rodriguez-Gonzalez A, Penalva V, Lucas L, Lacal JC. Inhibition of ChoK is an efficient antitumor strategy for Harvey-, Kirsten-, and N-ras-transformed cells. Biochem. Biophys. Res. Commun. 2001;285:873–879
  76. Taylor MT, Lawson KR, Ignatenko NA, Marek SE, Stringer DE, Skovan BA, et al. Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells. Cancer Res. 2000;60:6607–6610
  77. Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, et al. Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells. Mol. Cell Biol. 2002;22:8184–8198
  78. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell. 2002;2:243–247
  79. Nakada Y, Saito S, Ohzawa K, Morioka CY, Kita K, Minemura M, et al. Antisense oligonucleotides specific to mutated K-ras genes inhibit invasiveness of human pancreatic cancer cell lines. Pancreatology. 2001;1:314–319
  80. Su Z, Lebedeva IV, Gopalkrishnan RV, Goldstein NI, Stein CA, Reed JC, et al.  A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells. Proc. Natl. Acad. Sci. USA. 2001;98:10332–10337
  81. Zhang YA, Nemunaitis J, Scanlon KJ, Tong AW. Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice. Gene Ther. 2000;7:2041–2050
  82. Song JJ, Lee H, Kim E, Kim YS, Yoo NC, Roh JK, et al.  Transduction effect of antisense K-ras on malignant phenotypes in gastric cancer cells. Cancer Lett. 2000;157:1–7
  83. Lacal JC. Choline Kinase inhibitors: a novel target to search for antitumor drugs. Drugs. 2001;4:419–426
  84. Wittenberg J, Konberg A. Choline phosphokinase. J. Biol. Chem. 1953;202:431–444
  85. Lacal JC, Moscat J, Aaronson SA. Novel source of 1,2-duacylglicerol elevated in cells transformed by Ha-ras oncogene. Nature. 1987;330:269–271
  86. Lacal JC. Diacylglicerol production in Xenopus Laevis oocytes after microinjection of p21ras proteins is a consequence of activation of phosphatydilcholine metabolism. Mol. Cell Biol. 1990;10:333–340
  87. Macara IG. Elevated phosphocholine concentration in ras-transformed cells NIH3T3 cells arises from increase choline kinase activity, not from phosphatidylcholine breakdown. Mol. Cell Biol. 1989;9:325–328
  88. Ratnam S, Kent C. Early increase in choline kinase activity upon induction of the H-ras oncogene in mouse fibroblast cell lines. Arch. Biochem. Biophys. 1995;323:313–322
  89. Bhakoo KK, Williams SR, Florian CL, Land H, Noble M. Immortalization and transformation are associated with specific alterations in choline metabolism. Cancer Res. 1996;56:4630–4635
  90. Ramirez de Molina A, Penalva V, Lucas L, Lacal JC. Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K. Oncogene. 2002;21:937–946
  91. Jiménez B, del Peso L, Montaner S, Esteve P, Lacal JC. Generation of phosphorylcholine as an essential event in the activation of Raf-1 and MAP-Kinases in growth factors/induced mitogenic stimulation. J. Cell Biochem. 1995;57:141–149
  92. Kiss Z, Chung T. Choline phosphate and phosbol esters potentiate the mitogenic effect of insulin by competitive mechanism in NIH3T3 cells. Biochem. Biophys. Res. Commun. 1996;218:505–509
  93. Chung T, Crilly KS, Anderson WH, Murherjee JJ, Kiss Z. ATP-dependent choline phosphate-induced mitogenesis in fibroblasts involves activation of pp70 S6 kinase and phosphatydilinositol 3′-kinase through an extracellular site. J. Biol. Chem. 1997;272:3064–3072
  94. Huang JS, Mukherjee JJ, Chung T, Crilly KS, Kiss Z. Extracellular calcium stimulates DNA synthesis in synergism with zinc, insulin and insulin-like growth factor I infibroblasts. Eur. J. Biochem. 1999;266:943–951
  95. Chung T, Huang JS, Mukherjee JJ, Crilly KS, Kiss Z. Expression of human choline kinase in NIH 3T3 fibroblasts increases the mitogenic potential of insulin and insulin-like growth factor I. Cell Signal. 2000;12:279–288
  96. Warden CH, Friedkin M. Regulation of phosphatidylcholine biosynthesis by mitogenic growth factors. Biochim. Biophys. Acta. 1984;792:270–280
  97. Ruiz-Cabello J, Cohen JS. Phospholipid metabolites as indicators of cancer cell function. NMR Biomed. 1992;5:226–233
  98. de Certaines JD, Larsen VA, Podo F, Carpinelli G, Briot O, Henriksen O. In vivo 31P MRS of experimental tumours. NMR Biomed. 1993;6:345–365
  99. Smith TAD, Bush C, Jameson C, Titley JC, Leach MO, Wilman DEV, et al. Phospholipid metabolites, prognosis and proliferation in human breast carcinoma. NMR Biomed. 1993;6:318–323
  100. DeGrado TR, Baldwin SW, Wang S, Orr MD, Liao RP, Friedman HS, et al.  Synthesis and evaluation of [18]F-labeled choline analogs as oncologic PET tracers. J. Nucl. Med. 2001;42:1805–1814
  101. Hara T, Kosaka N, Kishi H. Development of [18]F-fluoroethylcholine for cancer imaging with PET: synthesis, biochemistry, and prostate cancer imaging. J. Nucl. Med. 2002;43:187–199
  102. Sharma V, Luker GD, Piwnica-Worms D. Molecular imaging of gene expression and protein function in vivo with PET and SPECT. J. Magn. Reson. Imaging. 2002;16:336–351
  103. Nakagami K, Uchida T, Ohwada S, Koibuchi Y, Morishita Y. Increased choline kinase activity in 1,2-dimethylhydrazine-induced rat colon cancer. Jpn. J. Cancer. Res. 1990;90:1212–1217
  104. Nakagami K, Uchida T, Ohwada S, Koibuchi Y, Suda Y, Sekine T, et al. Choline kinase activity and elevated phosphocholine levels in human colon cancer. Jpn. J. Cancer Res. 1999;90:419–424
  105. Ramı́rez de Molina A, Rodriguez-Gonzalez A, Gutierrez R, Martinez-Pineiro L, Sanchez JJ, Bonilla F, et al.  Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochem. Biophys. Res. Commun. 2002;296:580–583
  106. Ramı́rez de Molina A, Gutierrez R, Ramos MA, Silva JM, Silva J, Bonilla F, et al.  Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy. Oncogene. 2002;21:4317–4322
  107. Lloveras J, Hamza M, Chap H, Douste-Blazy L. Action of hemicholinium-3 on phospholipid metabolism in Krebs II ascites cells. Biochem. Pharmacol. 1985;34:3987–3993
  108. Cannon JG. Structure-activity aspects of hemicholinium-3 (HC-3) and its analogs and congeners. Med. Res. Rev. 1994;14:505–531
  109. Rodrı́guez-González A, Ramı́rez de Molina A, Fernández F, Ramos MA, Núñez MC, Campos J, et al.  Lacal Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells. Oncogene. 2003; in press
  110. A. Ramı́rez de Molina, M. Bánez, R. Gutiérrez, J.C. Lacal, A novel preclinical therapeutic modality in human-derived breast tumours: inhibition of choline kinase, submitted for publication.

PII: S0304-3835(03)00633-5

doi: 10.1016/j.canlet.2003.08.031

Cancer Letters
Volume 206, Issue 2 , Pages 137-148 , 8 April 2004