Inhibition of farnesyl protein-transferase in neuroblastoma cells by α-hydroxyfarnesylphosphonate

被引:0
|
作者
Girgert, R [1 ]
Hohnecker, A [1 ]
Wittrock, J [1 ]
Schweizer, P [1 ]
机构
[1] Univ Tubingen, Oncol Lab, Dept Pediat Surg, D-72076 Tubingen, Germany
关键词
farnesyl-transferase; membrane anchorage; neuroblastoma; ras;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Oncogenic Ras is responsible for malignant transformation in a variety of tumors. Farnesylation of Ras by farnesyl-protein-transferase (FPTase) is neccessary for membrane localization of Ras-proteins, a prerequisite for its biological activity. Although mutations in ras genes are rare in neuroblastoma inactivation of Ras by inhibition of the FPTase is of interest in neuroblastoma. In this tumor, amplification of N-myc is frequently observed and expression of N-myc is induced via Ras signaling. Farnesyl-protein-transferase of neuroblastoma cells is inhibited by alpha-hydroxyfarnesylphosphonate. In homogenates of the cell line SK-N-AS an ID50 = 6.5 mu M is estimated, in SK-N-SH the ID50 is 3.4 mu M. The consequences of the inhibition of FPTase on the membrane localization was examined by immunoblots. Western blots of membrane proteins analysed with H-ras and N-ras specific antibodies revealed that H-ms protein is more sensitive to the inhibition of FPTase than N-ras protein. After culturing neuroblastoma cells for 24 hrs in the presence of 20 mu M a-hydroxyfarnesylphosphonate H-ras protein completely dissappeared from the membrane fraction whereas N-ras protein was only affected by 50 %. K-ras was not detectable on Western blots of three neuroblastoma cell lines. The experiments showed that FPTase inhibitors are effective in neuroblastoma cells but for, complete inactivation of N-ras stronger conditions are required than for H-ras.
引用
收藏
页码:2959 / 2962
页数:4
相关论文
共 50 条
  • [41] Design and synthesis of novel Farnesyl protein transferase inhibitors
    Evans, DM
    Baxter, AJ
    Franklin, RJ
    Jenkins, PD
    Kendrick, DA
    Pitt, GR
    Rooker, DR
    Semple, G
    Ashworth, D
    Elliot, L
    Junien, JL
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1998, 215 : U914 - U914
  • [42] Inhibitors of farnesyl:protein transferase - A possible cancer chemotherapeutic
    Scholten, JD
    Zimmerman, K
    Oxender, M
    SeboltLeopold, J
    Gowan, R
    Leonard, D
    Hupe, DJ
    BIOORGANIC & MEDICINAL CHEMISTRY, 1996, 4 (09) : 1537 - 1543
  • [43] Chemical modification studies of yeast farnesyl protein transferase
    Sohn, SW
    Jun, G
    Yang, CH
    JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1997, 30 (04): : 280 - 284
  • [44] Subcellular distribution of farnesyl protein transferase in rat liver
    Grünler, J
    Parmryd, I
    FEBS LETTERS, 1999, 455 (03) : 233 - 237
  • [45] GENETIC INHIBITION OF P21RAS FARNESYL TRANSFERASE
    PRENDERGAST, GC
    DAVIDE, J
    DIEHL, R
    KRAL, A
    GIBBS, J
    OMER, C
    KOHL, N
    JOURNAL OF CELLULAR BIOCHEMISTRY, 1993, : 281 - 281
  • [46] Synthesis of a novel, selective and farnesyl pyrophosphate competitive farnesyl-protein transferase inhibitor
    Shibata, J
    Aoyama, T
    Kawakami, K
    Arai, S
    Iwasawa, Y
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1996, 212 : 54 - MEDI
  • [47] Crystal structure of farnesyl protein transferase complexed with a CaaX peptide and farnesyl diphosphate analogue
    Strickland, CL
    Windsor, WT
    Syto, R
    Wang, L
    Bond, R
    Wu, Z
    Schwartz, J
    Le, HV
    Beese, LS
    Weber, PC
    BIOCHEMISTRY, 1998, 37 (47) : 16601 - 16611
  • [48] Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate
    Troutman, JM
    Chehade, KAH
    Kiegiel, K
    Andres, DA
    Spielmann, HP
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (19) : 4979 - 4982
  • [49] Protein farnesyl transferase as a target for the development of anticancer drugs
    Adjei, AA
    DRUGS OF THE FUTURE, 2000, 25 (10) : 1069 - 1079
  • [50] INHIBITION OF RAS FUNCTION IN-VITRO AND IN-VIVO USING INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
    KOHL, NE
    WILSON, FR
    THOMAS, TJ
    BOCK, RL
    MOSSER, SD
    OLIFF, A
    GIBBS, JB
    SMALL GTPASES AND THEIR REGULATORS, PT A, 1995, 255 : 378 - 386