Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

A yeast-based genomic strategy highlights the cell protein networks altered by FTase inhibitor peptidomimetics

Authors: Giampiero Porcu, Cathal Wilson, Daniele Di Giandomenico, Antonella Ragnini-Wilson

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Background

Farnesyltransferase inhibitors (FTIs) are anticancer agents developed to inhibit Ras oncoprotein activities. FTIs of different chemical structure act via a conserved mechanism in eukaryotic cells. They have low toxicity and are active on a wide range of tumors in cellular and animal models, independently of the Ras activation state. Their ultimate mechanism of action, however, remains undetermined. FTase has hundred of substrates in human cells, many of which play a pivotal role in either tumorigenesis or in pro-survival pathways. This lack of knowledge probably accounts for the failure of FTIs at clinical stage III for most of the malignancies treated, with the notable exception of haematological malignancies. Understanding which cellular pathways are the ultimate targets of FTIs in different tumor types and the basis of FTI resistance is required to improve the efficacy of FTIs in cancer treatment.

Results

Here we used a yeast-based cellular assay to define the transcriptional changes consequent to FTI peptidomimetic administration in conditions that do not substantially change Ras membrane/cytosol distribution. Yeast and cancer cell lines were used to validate the results of the network analysis. The transcriptome of yeast cells treated with FTase inhibitor I was compared with that of untreated cells and with an isogenic strain genetically inhibited for FTase activity (Δram1). Cells treated with GGTI-298 were analyzed in a parallel study to validate the specificity of the FTI response. Network analysis, based on gene ontology criteria, identified a cell cycle gene cluster up-regulated by FTI treatment that has the Aurora A kinase IPL1 and the checkpoint protein MAD2 as hubs. Moreover, TORC1-S6K-downstream effectors were found to be down-regulated in yeast and mammalian FTI-treated cells. Notably only FTIs, but not genetic inhibition of FTase, elicited up-regulation of ABC/transporters.

Conclusions

This work provides a view of how FTIs globally affect cell activity. It suggests that the chromosome segregation machinery and Aurora A association with the kinetochore as well as TORC1-S6K downstream effectors are among the ultimate targets affected by the transcriptional deregulation caused by FTI peptidomimetics. Moreover, it stresses the importance of monitoring the MDR response in patients treated with FTIs.
Appendix
Available only for authorised users
Literature
1.
Casey PJ, Seabra MC: Protein prenyltransferases. J Biol Chem. 1996, 271: 5289-5292. 10.1074/jbc.271.10.5289CrossRefPubMed
2.
Tamanoi F, Mitsuzawa H: Use of yeast for identification of farnesyltransferase inhibitors and for generation of mutant farnesyltransferases. Methods Enzymol. 1995, 255: 82-91. full_textCrossRefPubMed
3.
Adjei AA: Farnesyltransferase inhibitors. Update on Cancer Therapeutics. 2006, 1: 17-23. 10.1016/j.uct.2006.05.005.CrossRef
4.
Appels NM, Beijnen JH, Schellens JH: Development of farnesyl transferase inhibitors: a review. Oncologist. 2005, 10: 565-578. 10.1634/theoncologist.10-8-565CrossRefPubMed
5.
Basso AD, Kirschmeier P, Bishop WR: Lipid posttranslational modifications. Farnesyl transferase inhibitors. J Lipid Res. 2006, 47: 15-31. 10.1194/jlr.R500012-JLR200CrossRefPubMed
6.
Lancet JE, Gojo I, Gotlib J, Feldman EJ, Greer J, Liesveld JL, Bruzek LM, Morris L, Park Y, Adjei AA, Kaufmann SH, Garrett-Mayer E, Greenberg PL, Wright JJ, Karp JE: A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myleogenous leukemia. Blood. 2007, 109: 1387-1394. 10.1182/blood-2006-04-014357PubMedCentralCrossRefPubMed
7.
Martin LA, Head JE, Pancholi S, Salter J, Quinn E, Detre S, Kaye S, Howes A, Dowsett M, Johnston SR: The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther. 2007, 6: 2458-2467. 10.1158/1535-7163.MCT-06-0452CrossRefPubMed
8.
Karp JE, Lancet JE: Tipifarnib in the treatment of newly diagnosed acute myelogenous leukemia. Biologics. 2008, 2: 491-500.PubMedCentralPubMed
9.
Sparano JA, Moulder S, Kazi A, Coppola D, Negassa A, Vahdat L, Li T, Pellegrino C, Fineberg S, Munster P, Malafa M, Lee D, Hoschander S, Hopkins U, Hershman D, Wright JJ, Kleer C, Merajver S, Sebti SM: Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer. Clin Cancer Res. 2009, 15: 2942-2948. 10.1158/1078-0432.CCR-08-2658PubMedCentralCrossRefPubMed
10.
Kho Y, Kim SC, Jiang C, Barma D, Kwon SW, Cheng J, Jaunbergs J, Weinbaum C, Tamanoi F, Falck J, Zhao Y: A tagging-via-substrate technology for detections and proteomics of farnesylated proteins. Proc Natl Acad Sci. 2004, 101: 12479-12484. 10.1073/pnas.0403413101PubMedCentralCrossRefPubMed
11.
Ashar HR, James L, Gray K, Carr D, Black S, Armstrong L, Bishop WR, Kirschmeier P: Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem. 2000, 275: 30451-30457. 10.1074/jbc.M003469200CrossRefPubMed
12.
Crespo NC, Ohkanda J, Yen TJ, Hamilton AD, Sebti SM: The farnesyltransferase inhibitor, FTI-2153 blocks bipolar spindle formation and chromosome alignement and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem. 2001, 276: 16161-16167. 10.1074/jbc.M006213200CrossRefPubMed
13.
Schafer-Hales K, Iaconelli J, Snyder JP, Prussia A, Nettles JH, El-Naggar A, Khuri FR, Giannakakou P, Marcus AI: Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function. Mol Cancer Ther. 2007, 6: 1317-1328. 10.1158/1535-7163.MCT-06-0703CrossRefPubMed
14.
Zujewski J, Horak ID, Bol CJ, Woestenborghs R, Bowden C, End DW, Piotrovsky VK, Chiao J, Belly RT, Todd A, Kopp WC, Kohler DR, Chow C, Noone M, Hakim FT, Larkin G, Gress RE, Nussenblatt RB, Kremer AB, Cowan KH: Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol. 2000, 18: 927-941.PubMed
15.
Raponi M, Harousseau JL, Lancet JE, Löwenberg B, Stone R, Zhang Y, Rackoff W, Wang Y, Atkins D: Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res. 2007, 13: 2254-2260. 10.1158/1078-0432.CCR-06-2609CrossRefPubMed
16.
Baetz K, McHardy L, Gable K, Tarling T, Rebérioux D, Bryan J, Andersen RJ, Dunn T, Hieter P, Roberge M: Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action. Proc Natl Acad Sci USA. 2004, 101: 4525-4530. 10.1073/pnas.0307122101PubMedCentralCrossRefPubMed
17.
Lum PY, Armour CD, Stepaniants SB, Cavet G, Wolf MK, Butler JS, Hinshaw JC, Garnier P, Prestwich GD, Leonardson A, Garrett-Engele P, Rush CM, Bard M, Schimmack G, Phillips JW, Roberts CJ, Shoemaker DD: Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell. 2004, 116: 121-137. 10.1016/S0092-8674(03)01035-3CrossRefPubMed
18.
Perlstein EO, Ruderfer DM, Roberts DC, Schreiber SL, Kruglyak L: Genetic basis of individual differences in the response to small-molecule drugs in yeast. Nat Genet. 2007, 39: 496-502. 10.1038/ng1991CrossRefPubMed
19.
McCue PP, Phang JM: Identification of human intracellular targets of the medicinal Herb St. John's Wort by chemical-genetic profiling in yeast. J Agric Food Chem. 2008, 56: 11011-11017. 10.1021/jf801593aPubMedCentralCrossRefPubMed
20.
Brunner TB, Hahan SM, Gupta AK, Muschel RJ, McKenna G, Bernhard EJ: Farnesyltransferase Inhibitors: An Overview of the results of preclinical and Clinical Investigation. Cancer Res. 2003, 63: 5656-5668.PubMed
21.
Cox AD, Garcia AM, Westwick JK, Kowalczyk JJ, Lewis MD, Brenner DA, Der CJ: The CAAX peptidomimetic compound B581 specifically blocks farnesylated, but not geranylgeranylated or myristylated, oncogenic ras signaling and transformation. J Biol Chem. 1994, 269: 19203-19206.PubMed
22.
Doisneau-Sixou SF, Cestac P, Faye JC, Favre G, Sutherland RL: Additive effects of tamoxifen and the farnesyl transferase inhibitor FTI-277 on inhibition of MCF-7 breast cancer cell-cycle progression. Int J Cancer. 2003, 106: 789-798. 10.1002/ijc.11263CrossRefPubMed
23.
Yamaguchi M, Zhou C, Nanda A, Zhang JH: Ras protein contributes to cerebral vasospasm in a canine double-hemorrhage model. Stroke. 2004, 35: 1750-1755. 10.1161/01.STR.0000129898.68350.9fCrossRefPubMed
24.
Zhang B, Groffen J, Heisterkamp N: Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a. Blood. 2005, 106: 1355-1361. 10.1182/blood-2004-09-3655PubMedCentralCrossRefPubMed
25.
Petronczki M, Siomos MF, Nasmyth K: Un ménage à quatre: the molecular biology of chromosome segregation in meiosis. Cell. 2003, 112: 423-440. 10.1016/S0092-8674(03)00083-7CrossRefPubMed
26.
Mamnun YM, Schüller C, Kuchler K: Expression regulation of the yeast PDR5 ATP-binding cassette (ABC) transporter suggests a role in cellular detoxification during the exponential growth phase. FEBS Letters. 2004, 559: 111-117. 10.1016/S0014-5793(04)00046-8CrossRefPubMed
27.
Wang E, Casciano CN, Clement RP, Johnson WW: The farnesyl protein transferase inhibitor SCH66336 is a potent inhibitor of MDR1 product P-glycoprotein. Cancer Res. 2001, 61: 7525-7529.PubMed
28.
Katayama K, Yoshioka S, Tsukahara S, Mitsuhashi J, Sugimoto Y: Inhibition of the mitogen-activated protein kinase pathway results in the down-regulation of P-glycoprotein. Mol Cancer Ther. 2007, 6: 2092-2102. 10.1158/1535-7163.MCT-07-0148CrossRefPubMed
29.
Yun J, Rago C, Cheong I, Paglierini R, Angenendt P, Rajagopalan H, Schmidt K, Willson JK, Markowitz S, Zhou S, Diaz LA, Velculescu VE, Lengauer C, Kinzler KW, Vogelstein B, Papadopoulos N: Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009, 325: 1555-1559. 10.1126/science.1174229PubMedCentralCrossRefPubMed
30.
Greatrix BW, Van Vuuren HJ: Expression of the HXT13, HXT15 and HXT17 genes in Saccharomyces cerevisiae and stabilization of the HXT1 gene transcript by sugar-induced osmotic stress. Curr Genet. 2006, 49: 205-217. 10.1007/s00294-005-0046-xCrossRefPubMed
31.
Nourani A, Wesolowski-Louvel M, Delaveau T, Jacq C, Delahodde A: Multi-drug-resistance phenomenon in the yeast Saccharomyces cerevisiae: involvement of two hexose transporters. Mol Cell Biol. 1997, 17: 5453-5460.PubMedCentralCrossRefPubMed
32.
Plemper RK, Egner R, Kuchler K, Wolf DH: Endoplasmic reticulum degradation of a mutated ATP-binding cassette transporter Pdr5 proceeds in a concerted action of Sec61 and the proteasome. J Biol Chem. 1998, 273: 32848-32856. 10.1074/jbc.273.49.32848CrossRefPubMed
33.
Egner R, Mahé Y, Pandjaitan R, Kuchler K: Endocytosis and vacuolar degradation of the plasma membrane-localized Pdr5 ATP-binding cassette multidrug transporter in Saccharomyces cerevisiae. Mol Cell Biol. 1995, 15: 5879-5887.PubMedCentralCrossRefPubMed
34.
Cameroni E, Hulo N, Roosen J, Winderickx J, De Virgilio C: The novel yeast PAS kinase Rim 15 orchestrates G0-associated antioxidant defense mechanisms. Cell cycle. 2004, 3: 462-468.CrossRefPubMed
35.
Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, Longo VD: Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet. 2008, 4: e13- 10.1371/journal.pgen.0040013PubMedCentralCrossRefPubMed
36.
Powers T: TOR Signaling and S6 Kinase 1: Yeast Catches Up. Cell Metabolism. 2007, 6: 1-2. 10.1016/j.cmet.2007.06.009CrossRefPubMed
37.
Urban J, Soulard A, Huber A, Lippman S, Mukhopadhyay D, Deloche O, Wanke V, Anrather D, Ammerer G, Riezman H, Broach JR, De Virgilio C, Hall MN, Loewith R: Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. Mol Cell. 2007, 26: 663-674. 10.1016/j.molcel.2007.04.020CrossRefPubMed
38.
Karbowniczek M, Spittle CS, Morrison T, Wu H, Henske EP: mTOR is activated in the majority of malignant melanomas. J Invest Dermatol. 2008, 128: 980-987. 10.1038/sj.jid.5701074CrossRefPubMed
39.
Basso AD, Mirza A, Liu G, Long BJ, Bishop WR, Kirschmeier P: The Farnesyl Transferase Inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem. 2005, 280: 31101-31108. 10.1074/jbc.M503763200CrossRefPubMed
40.
Fox GC, Shafiq M, Briggs DC, Knowles PP, Collister M, Didmon MJ, Makrantoni V, Dickinson RJ, Hanrahan S, Totty N, Stark MJR, Keyse SM, McDonald NQ: Redox-mediated substrate recognition by Sdp1 defines a new group of tyrosine phosphatases. Nature. 2007, 447: 487-492. 10.1038/nature05804CrossRefPubMed
41.
Chen RE, Thorner J: Function and regulation in MAPK signaling pathways: lessons learned from the yeast Saccharomyces cerevisiae. Biochim Biophys Acta. 2007, 1773: 1311-1340. 10.1016/j.bbamcr.2007.05.003PubMedCentralCrossRefPubMed
42.
Hahn JS, Thiele DJ: Regulation of the Saccharomyces cerevisiae Slt2 kinase pathway by the stress-inducible Sdp1 dual specificity phosphatase. J Biol Chem. 2002, 277: 21278-21284. 10.1074/jbc.M202557200CrossRefPubMed
43.
Heymont J, Berenfeld L, Collins J, Kaganovich A, Maynes B, Moulin A, Ratskovskaya I, Poon PP, Johnston GC, Kamenetsky M, DeSilva J, Sun H, Petsko GA, Engebrecht J: TEP1, the yeast homolog of the human tumor suppressor gene PTEN/MMAC1/TEP1, is linked to the phosphatidylinositol pathway and plays a role in the developmental process of sporulation. Proc Natl Acad Sci USA. 2000, 97: 12672-12677. 10.1073/pnas.97.23.12672PubMedCentralCrossRefPubMed
44.
Schmidt A, Schmelzle T, Hall MN: The RHO1-GAPs SAC7, BEM2 and BAG7 control distinct RHO1 functions in Saccharomyces cerevisiae. Mol Microbiol. 2002, 45: 1433-1441. 10.1046/j.1365-2958.2002.03110.xCrossRefPubMed
45.
Durkin ME, Yuan BZ, Zhou X, Zimonjic DB, Lowy DR, Thorgeirsson SS, Popescu NC: DLC-1:a Rho GTPase-activating protein and tumour suppressor. J Cell Mol Med. 2007, 11: 1185-1207. 10.1111/j.1582-4934.2007.00098.xPubMedCentralCrossRefPubMed
46.
Francisco L, Chan CS: Regulation of yeast chromosome segregation by Ipl1 protein kinase and type 1 protein phosphatase. Cell Mol Biol Res. 1994, 40: 207-213.PubMed
47.
Tanaka M, Ueda A, Kanamori H, Ideguchi H, Yang J, Kitajima S, Ishigatsubo Y: Cell-cycle-dependent regulation of human aurora A transcription is mediated by periodic repression of E4TF1. J Biol Chem. 2002, 277: 10719-10726. 10.1074/jbc.M108252200CrossRefPubMed
48.
Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A, Rosen N: A peptidomimetic inhibitor of Farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res. 1995, 55: 5302-5309.PubMed
49.
Medeiros BC, Landau HJ, Morrow M, Lockerbie RO, Pitts T, Eckardt SG: The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines. Leukemia. 2007, 21: 739-746.PubMed
50.
Wagner W, Bielli P, Wacha S, Ragnini-Wilson A: Mlc1p promotes septum closure during cytokinesis via the IQ motifs of the vesicle motor Myo2p. EMBO J. 2002, 21: 6397-6408. 10.1093/emboj/cdf650PubMedCentralCrossRefPubMed
51.
Bielli P, Casavola EC, Biroccio A, Urbani A, Ragnini-Wilson A: GTP drives myosin light chain 1 interaction with the class V myosin Myo2 IQ motifs via a Sec2 RabGEF-mediated pathway. Mol Microbiol. 2006, 59: 1576-1590. 10.1111/j.1365-2958.2006.05041.xCrossRefPubMed
52.
Ausubel FM, Brent R, Kingston RE, Moore DD, Seidman JG, Smith JA, Struhl K: Preparation of yeast RNA. Current Protocols in Molecular Biology. 1994, 2: 13.12.1, Greene Publishing Associates and Wiley-Interscience,
53.
Bialek-Wyrzykowska U, Bauer BE, Wagner W, Kohlwein SD, Schweyen RJ, Ragnini A: Low levels of Ypt protein prenylation cause vesicle polarization defects and thermosensitive growth that can be suppressed by genes involved in cell wall maintenance. Mol Microbiol. 2000, 35: 1295-1311. 10.1046/j.1365-2958.2000.01782.xCrossRefPubMed
Metadata
Title
A yeast-based genomic strategy highlights the cell protein networks altered by FTase inhibitor peptidomimetics
Authors
Giampiero Porcu
Cathal Wilson
Daniele Di Giandomenico
Antonella Ragnini-Wilson
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-197

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

XIAP gene expression and function is regulated by autocrine and paracrine TGF-β signaling

Research

Regulation of the Aurora-A gene following topoisomerase I inhibition: implication of the Myc transcription Factor

Review

Roles of Sema4D and Plexin-B1 in tumor progression

Research

Identification of 5 novel genes methylated in breast and other epithelial cancers

Research

t-DARPP regulates phosphatidylinositol-3-kinase-dependent cell growth in breast cancer

Research

Evaluation of LMP1 of Epstein-Barr virus as a therapeutic target by its inhibition
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits