Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice

Oncogene volume 18, pages 2579–2588 (1999)Cite this article

Abstract

Constitutively active Ras proteins, their regulatory components, and overexpressed tyrosine kinase receptors that activate Ras, are frequently associated with cell transformation in human tumors. This suggests that functional Ras antagonists may have anti-tumor activity. Studies in rodent fibroblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather specific nontoxic Ras antagonist, dislodging Ras from its membrane anchorage domains and accelerating its degradation. FTS is not a farnesyltransferase inhibitor, and does not affect Ras maturation. Here we demonstrate that FTS also acts as a functional Ras antagonist in human pancreatic cell lines that express activated K-Ras (Panc-1 and MiaPaCa-2). In Panc-1 cells, FTS at a concentration of 25 – 100 μM reduced the amount of Ras in a dose-dependent manner and interfered with serum-dependent and epidermal growth factor-stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage-independent growth of Panc-1 cells in vitro. FTS also inhibited tumor growth in Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS treatment (5 mg/kg intraperitoneally) in mice with tumors (mean volume 0.07 cm3) markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23±30-fold in the FTS-treated group and by 127±66-fold in controls). These findings suggest that FTS represents a new class of functional Ras antagonists with potential therapeutic value.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Aharonson Z, Gana-Weisz M, Varsano T, Haklai H, Marciano D and Kloog Y. . 1998 Biochim. Biophys. Acta 1406: 40–50.

  • Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N and Perucho M. . 1988 Cell 53: 549–554.

    Article  CAS  Google Scholar 

  • Barbacid M. . 1987 Annu. Rev. Biochem. 56: 779–827.

    Article  CAS  Google Scholar 

  • Berrozpe G, Schaeffer J, Peinado MA, Real FX and Perucho M. . 1994 Int. J. Cancer 58: 185–191.

    Article  CAS  Google Scholar 

  • Boguski MS and McCormick F. . 1993 Nature 366: 643–654.

    Article  CAS  Google Scholar 

  • Bos JL. . 1989 Cancer Res. 49: 4682–4689.

  • Bos JL. . 1995 Eur. J. Cancer 31A: 1051–1054.

  • Bos JL. . 1997 Biochim. Biophys. Acta 1333: M19–M31.

  • Casey PJ, Solski PA, Der CJ and Buss JE. . 1989 Proc. Natl. Acad. Sci. USA 86: 8323–8327.

  • Chen YF, Pan G-Z, Hou X, Liu T-H, Chen L, Yanaihara C and Yanaihara N. . 1990 Pancreas 5: 278–283.

    Article  CAS  Google Scholar 

  • Cobb MH and Goldsmith EJ. . 1995 J. Biol. Chem. 270: 14843–14846.

    Article  CAS  Google Scholar 

  • Cox AD and Der CJ. . 1992 Curr. Opin. Cell. Biol. 4: 1008–1016.

  • Cox AD and Der CJ. . 1997 Biochim. Biophys. Acta 1333: F51–F71.

  • Dhanasekaran N, Heasley E and Johnson GL. . 1995 Endocr. Rev. 16: 259–270.

  • Fearon ER. . 1997 Science 278: 1043–1049.

    Article  CAS  Google Scholar 

  • Fransworth CL, Frenshney MW, Rosen LB, Ghosh A, Greenberg ME and Feig LA. . 1995 Nature 376: 524–527.

    Article  CAS  Google Scholar 

  • Gana-Weisz M, Haklai R, Marciano D, Egozi Y, Ben-Baruch G and Kloog Y. . 1997 Biochem. Biophys. Res. Commun. 239: 900–904.

  • Gibbs JB and Oliff A. . 1997 Ann. Rev. Pharmacol. Toxicol. 37: 146–166.

    Article  CAS  Google Scholar 

  • Gutierrez L, Magee AL, Marshall CJ and Hancock JF. . 1989 EMBO J. 8: 1093–1098.

  • Haklai R, Gana-Weisz M, Elad G, Marciano D, Egozi Y, Ben-Baruch G and Kloog Y. . 1998 Biochemistry 37: 1306–1314.

    Article  CAS  Google Scholar 

  • Hall A. . 1998 Science 279: 509–514.

    Article  CAS  Google Scholar 

  • Hancock JF, Cadwallader K, Paterson H and Marshall CJ. . 1991 EMBO J. 10: 4033–4039.

  • Hancock JF, Magee AI, Childs JE and Marshall CJ. . 1989 Cell 57: 1167–1177.

    Article  CAS  Google Scholar 

  • Huang HJ, Nagane M, Klingbell CK, Lin H, Nishikawa R, Ji X-D, Huang C-M, Gill GN, Wiley HS and Cavenee WK . 1997 J. Biol. Chem. 272: 2927–2935.

    Article  CAS  Google Scholar 

  • Hubran RH, van Mansfeld ADM, Offerhause GJA, van Weering DHJ, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL and Bos JL. . 1993 Am. J. Pathol. 143: 545–554.

  • James GL, Goldstein JL, Rawson TE, Somers TC, McDowell RS, Crowley CW, Lucas BK, Levinson AD and Masters Jr CJ. . 1993 Science 260: 1937–1942.

    Article  CAS  Google Scholar 

  • James G, Goldstein JL and Brown MS. . 1996 Proc. Natl. Acad. Sci. USA 93: 4454–4458.

  • Khosravi-Far R, Campbell S, Rossman KL and Der CJ. . 1998 Adv. Cancer Res. 72: 57–107.

  • Kinoshita T, Yokota T, Arai K and Miyajima A. . 1995 Oncogene 10: 2207–2212.

  • Kohl NE, Mosser SD, DeSolms SJ, Giuliani EA, Pompliano DL, Graham SL, Smith RL, Scolnick EM, Oliff A and Gibbs JB. . 1993 Science 260: 1937–1937.

    Article  CAS  Google Scholar 

  • Kohl NE, Wilson FR, Mosser SD, Giuliani E, DeSolms SJ, Conner MW, Anthony NJ, Holz WJ, Gomez RP and Lee TJ. . 1994 Proc. Natl. Acad. Sci. USA 91: 9141–9145.

  • Koleske AJ, Baltimore D and Lisanti M. . 1995 Proc. Natl. Acad. Sci. USA 92: 1381–1385.

  • Kolibaba KS and Druker BJ. . 1997 Biochim. Biophys. Acta 1333: F217–F248.

  • Korc M, Meltzer P and Trent J. . 1986 Proc. Natl. Acad. Sci. USA 83: 5141–5144.

  • Kundra V, Anand Apte B, Feig LA and Zetter BR. . 1995 J. Cell. Biol. 130: 725–731.

  • Lange-Carter CA and Johnson GL. . 1994 Science 265: 1458–1461.

    Article  CAS  Google Scholar 

  • Lebowitz PF, Sakamuro D and Prendergast GC. . 1997 Cancer Res. 57: 708–713.

  • Lemoine NR, Hughes CM, Barton CM, Poulsom R, Jeffrey RE, Kloppel G, Hall PA and Gullick WA. . 1992 J. Pathol. 166: 7–12.

    Article  CAS  Google Scholar 

  • Lisanti MP, Scherer PE, Tang Z and Sargiacomo M. . 1994 Trends Cell Biol. 4: 231–235.

  • Lowry DR and Wilumsen BM. . 1993 Annu. Rev. Biochem. 62: 851–891.

    Article  CAS  Google Scholar 

  • Manne V, Yan N, Carboni JM, Tuomari AV, Ricca CS, Brown JG, Andahazy ML, Schmidt RJ, Patel D and Zahler R. . 1995 Oncogene 10: 1763–1779.

  • Marciano D, Aharonson Z, Varsano T, Haklai R and Kloog Y. . 1997 Bioorg. Med. Chem. Lett. 7: 1709–1714.

  • Marciano D, Ben-Baruch G, Marom M, Egozi Y, Haklai R and Kloog Y. . 1995 J. Med. Chem. 38(8): 1267–1272.

    Article  CAS  Google Scholar 

  • Marom M, Haklai R, Ben-Baruch G, Marciano D, Egozi Y and Kloog Y. . 1995 J. Biol. Chem. 270: 22263–22270.

    Article  CAS  Google Scholar 

  • Marshall CJ. . 1996 Curr. Opin. Cell Biol. 8: 197–204.

  • McCormick F. . 1993 Nature 363: 15–16.

    Article  CAS  Google Scholar 

  • Meimbrook DC and Oliff A. . 1998 Curr. Opin. Cell Biol. 10: 284–288.

  • Mineo C, James GL, Smart EJ and Anderson GW. . 1996 J. Biol. Chem. 271: 11930–11935.

    Article  CAS  Google Scholar 

  • Nagasu Y, Yoshimatsu K, Rowell C, Lewis MD and Garcia AM. . 1995 Cancer Res. 55: 3510–3514.

  • Pellegata NS, Sessa F, Renault B, Bonato M, Leone BE, Solcia E and Ranzani GN. . 1994 Cancer Res. 54: 1556–1560.

  • Rall CJN, Yan Y-X, Graeme-Cook F, Beauchamp R, Yandell DW, Povoski SP and Rustgi AK. . 1996 Pancreas 12: 10–17.

  • Rodriguiez-Viciana P, Warne PH, Khawaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A and Downward J. . 1997 Cell 89: 457–467.

    Article  CAS  Google Scholar 

  • Rowell CA, Kowalczyk JJ, Lewis MD and Garcia AM. . 1997 J. Biol. Chem. 272: 14093–14097.

    Article  CAS  Google Scholar 

  • Salomon DS, Brandt R, Ciardiello F and Noramanno N. . 1995 Crit. Rev. Oncol. Hematol. 19: 183–232.

  • Scheffzek K, Ahmedian MR, Kabsch W, Wiesmuller L, Lawtwein A, Schmitz F and Wittinghofer A. . 1997 Science 277: 333–337.

  • Seger R, Ahn NG, Boulton TG, Yancopoulos GD, Panayotatos N, Radziejewska E, Ericsson L, Bratlien RL, Cobb MH and Krebs EG. . 1991 Proc. Natl. Acad. Sci. USA 88: 6142–6146.

  • Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A and Rosen N. . 1995 Cancer Res. 55: 5302–5309.

  • Siddiqui AA, Garland JR, Dalton MB and Sinensky M. . 1998 J. Biol. Chem. 273: 3712–3717.

    Article  CAS  Google Scholar 

  • Simons K and Ikonen E. . 1997 Nature 387: 569–572.

    Article  CAS  Google Scholar 

  • Smith JJ, Derynck R and Korc M. . 1987 Proc. Natl. Acad. Sci. USA 84: 7567–7570.

  • Song KS, Li S, Okamoto T, Quilliam LA, Sargiacomo M and Lisanti MP. . 1996 J. Biol. Chem. 271: 9690–9697.

    Article  CAS  Google Scholar 

  • Sun J, Qian Y, Hamilton AD and Sebti SM. . 1995 Cancer Res. 55: 4243–44247.

  • Symons M. . 1996 TIBS 21: 178–181.

  • Trent JC, McConkey DJ, Loughlin SM, Harbison MT, Fernandez A and Ananthaswamy HN. . 1996 EMBO J. 15: 4497–4505.

  • Whyte DB, Kirschmeier P, Hockenberry TN, Nunez-Olivia I, James L, Catino JJ, Bishop WR and Pai JK. . 1997 J. Biol. Chem. 272: 14459–14464.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S Smith for editorial assistance. This work was supported by a grant from the Israel Science Foundation (646 – 16.1) and in part by the Israel Cancer Research Foundation and the SAFAHO Foundation.

Author information

Authors and Affiliations

  1. Department of Neurobiochemistry, The George S Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, 69978, Israel

    Boaz Weisz, Mali Gana-Weisz, Yaakov Egozi & Yoel Kloog

  2. Department of Pharmacology and Toxicology, University of Ulm, Germany

    Klaudia Giehl & Peter Gierschik

  3. Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel

    Gilad Ben-Baruch

  4. Israel Institute for Biological Research, POB. 19, Ness-Ziona, 70450, Israel

    Daniela Marciano

Authors
  1. Boaz Weisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Klaudia Giehl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mali Gana-Weisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yaakov Egozi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gilad Ben-Baruch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniela Marciano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Gierschik
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoel Kloog
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weisz, B., Giehl, K., Gana-Weisz, M. et al. A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice. Oncogene 18, 2579–2588 (1999). https://doi.org/10.1038/sj.onc.1202602

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202602

Keywords

This article is cited by

Search

Advanced search

Quick links