Rho GTPases as therapeutic targets in cancer (Review)
- Authors:
- G. A. Cardama
- N. Gonzalez
- J. Maggio
- P. Lorenzano Menna
- D. E. Gomez
-
Affiliations: Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Bernal B1876BXD, Buenos Aires, Argentina - Published online on: August 9, 2017 https://doi.org/10.3892/ijo.2017.4093
- Pages: 1025-1034
-
Copyright: © Cardama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
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Abstract
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|
Marei H and Malliri A: Rac1 in human diseases: The therapeutic potential of targeting Rac1 signaling regulatory mechanisms. Small GTPases. Jul 21–2016.Epub ahead of print. PubMed/NCBI | |
|
Feltri ML, Suter U and Relvas JB: The function of RhoGTPases in axon ensheathment and myelination. Glia. 56:1508–1517. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Wuichet K and Søgaard-Andersen L: Evolution and diversity of the Ras superfamily of small GTPases in prokaryotes. Genome Biol Evol. 7:57–70. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Ramos S, Khademi F, Somesh BP and Rivero F: Genomic organization and expression profile of the small GTPases of the RhoBTB family in human and mouse. Gene. 298:147–157. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Leung KF, Baron R, Ali BR, Magee AI and Seabra MC: Rab GTPases containing a CAAX motif are processed post-geranylgeranylation by proteolysis and methylation. J Biol Chem. 282:1487–1497. 2007. View Article : Google Scholar | |
|
Aicart-Ramos C, Valero RA and Rodriguez-Crespo I: Protein palmitoylation and subcellular trafficking. Biochim Biophys Acta. 1808:2981–2994. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Shinde SR and Maddika S: Post translational modifications of Rab GTPases. Small GTPases. Feb 28–2017.Epub ahead of print. View Article : Google Scholar : PubMed/NCBI | |
|
Ulu A and Frost JA: Regulation of RhoA activation and cytoskeletal organization by acetylation. Small GTPases. 7:76–81. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Martin E, Ouellette MH and Jenna S: Rac1/RhoA antagonism defines cell-to-cell heterogeneity during epidermal morphogenesis in nematodes. J Cell Biol. 215:483–498. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Sahai E and Marshall CJ: RHO-GTPases and cancer. Nat Rev Cancer. 2:133–142. 2002. View Article : Google Scholar | |
|
Takai Y, Sasaki T and Matozaki T: Small GTP-binding proteins. Physiol Rev. 81:153–208. 2001.PubMed/NCBI | |
|
Kjøller L and Hall A: Signaling to Rho GTPases. Exp Cell Res. 253:166–179. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Symons M: The Rac and Rho pathways as a source of drug targets for Ras-mediated malignancies. Curr Opin Biotechnol. 6:668–674. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Griner EM, Caino MC, Sosa MS, Colón-González F, Chalmers MJ, Mischak H and Kazanietz MG: A novel crosstalk in diacylglycerol signaling: The Rac-GAP β2-chimaerin is negatively regulated by protein kinase Cdelta-mediated phosphorylation. J Biol Chem. 285:16931–16941. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Bustos RI, Forget MA, Settleman JE and Hansen SH: Coordination of Rho and Rac GTPase function via p190B RhoGAP. Curr Biol. 18:1606–1611. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Rosenfeldt H, Castellone MD, Randazzo PA and Gutkind JS: Rac inhibits thrombin-induced Rho activation: Evidence of a Pak-dependent GTPase crosstalk. J Mol Signal. 1:8. 2006. View Article : Google Scholar | |
|
Jaffe AB and Hall A: Rho GTPases: Biochemistry and biology. Annu Rev Cell Dev Biol. 21:247–269. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Kyrkou A, Soufi M, Bahtz R, Ferguson C, Bai M, Parton RG, Hoffmann I, Zerial M, Fotsis T and Murphy C: RhoD participates in the regulation of cell-cycle progression and centrosome duplication. Oncogene. 32:1831–1842. 2013. View Article : Google Scholar | |
|
Wei L, Surma M, Shi S, Lambert-Cheatham N and Shi J: Novel insights into the roles of Rho kinase in cancer. Arch Immunol Ther Exp (Warsz). 64:259–278. 2016. View Article : Google Scholar | |
|
Bartolini F, Moseley JB, Schmoranzer J, Cassimeris L, Goode BL and Gundersen GG: The formin mDia2 stabilizes microtubules independently of its actin nucleation activity. J Cell Biol. 181:523–536. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Reicher B, Joseph N, David A, Pauker MH, Perl O and Barda-Saad M: Ubiquitylation-dependent negative regulation of WASp is essential for actin cytoskeleton dynamics. Mol Cell Biol. 32:3153–3163. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S and Mizuno K: Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem. 275:3577–3582. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Lian G and Sheen VL: Cytoskeletal proteins in cortical development and disease: Actin associated proteins in periventricular heterotopia. Front Cell Neurosci. 9:992015. View Article : Google Scholar : PubMed/NCBI | |
|
Malarkannan S, Awasthi A, Rajasekaran K, Kumar P, Schuldt KM, Bartoszek A, Manoharan N, Goldner NK, Umhoefer CM and Thakar MS: IQGAP1: A regulator of intracellular spacetime relativity. J Immunol. 188:2057–2063. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Belletti B and Baldassarre G: Stathmin: A protein with many tasks. New biomarker and potential target in cancer. Expert Opin Ther Targets. 15:1249–1266. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Bishop AL and Hall A: Rho GTPases and their effector proteins. Biochem J. 348:241–255. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Miyano K and Sumimoto H: Assessment of the role for Rho family GTPases in NADPH oxidase activation. Methods Mol Biol. 827:195–212. 2012. View Article : Google Scholar | |
|
David M, Petit D and Bertoglio J: Cell cycle regulation of Rho signaling pathways. Cell Cycle. 11:3003–3010. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, et al: Role of YAP/TAZ in mechanotransduction. Nature. 474:179–183. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Porter AP, Papaioannou A and Malliri A: Deregulation of Rho GTPases in cancer. Small GTPases. 7:123–138. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, et al: A landscape of driver mutations in melanoma. Cell. 150:251–263. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, et al: Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 44:1006–1014. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Rossman KL, Der CJ and Sondek J: GEF means go: Turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 6:167–180. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Fields AP and Justilien V: The guanine nucleotide exchange factor (GEF) Ect2 is an oncogene in human cancer. Adv Enzyme Regul. 50:190–200. 2010. View Article : Google Scholar : | |
|
Vigil D, Cherfils J, Rossman KL and Der CJ: Ras superfamily GEFs and GAPs: Validated and tractable targets for cancer therapy? Nat Rev Cancer. 10:842–857. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Jarzynka MJ, Hu B, Hui KM, Bar-Joseph I, Gu W, Hirose T, Haney LB, Ravichandran KS, Nishikawa R and Cheng SY: ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion. Cancer Res. 67:7203–7211. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Wertheimer E, Gutierrez-Uzquiza A, Rosemblit C, Lopez-Haber C, Sosa MS and Kazanietz MG: Rac signaling in breast cancer: A tale of GEFs and GAPs. Cell Signal. 24:353–362. 2012. View Article : Google Scholar : | |
|
Khosravi-Far R, Solski PA, Clark GJ, Kinch MS and Der CJ: Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 15:6443–6453. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Qiu RG, Chen J, McCormick F and Symons M: A role for Rho in Ras transformation. Proc Natl Acad Sci USA. 92:11781–11785. 1995. View Article : Google Scholar : PubMed/NCBI | |
|
Sahai E and Marshall CJ: Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol. 5:711–719. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Wolf K, Mazo I, Leung H, Engelke K, von Andrian UH, Deryugina EI, Strongin AY, Bröcker EB and Friedl P: Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of pericellular proteolysis. J Cell Biol. 160:267–277. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Nakaya Y, Kuroda S, Katagiri YT, Kaibuchi K and Takahashi Y: Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1. Dev Cell. 7:425–438. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Lv Z, Hu M, Zhen J, Lin J, Wang Q and Wang R: Rac1/AK1 signaling promotes epithelial-mesenchymal transition of podocytes in vitro via triggering β-catenin transcriptional activity under high glucose conditions. Int J Biochem Cell Biol. 45:255–264. 2013. View Article : Google Scholar | |
|
Fritz G, Just I and Kaina B: Rho GTPases are over-expressed in human tumors. Int J Cancer. 81:682–687. 1999. View Article : Google Scholar : PubMed/NCBI | |
|
Engers R, Ziegler S, Mueller M, Walter A, Willers R and Gabbert HE: Prognostic relevance of increased Rac GTPase expression in prostate carcinomas. Endocr Relat Cancer. 14:245–256. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Lin Y and Zheng Y: Approaches of targeting Rho GTPases in cancer drug discovery. Expert Opin Drug Discov. 10:991–1010. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Gómez del Pulgar T, Benitah SA, Valerón PF, Espina C and Lacal JC: Rho GTPase expression in tumourigenesis: Evidence for a significant link. BioEssays. 27:602–613. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Liu Y, Song N, Ren K, Meng S, Xie Y, Long Q, Chen X and Zhao X: Expression loss and revivification of RhoB gene in ovary carcinoma carcinogenesis and development. PLoS One. 8:e784172013. View Article : Google Scholar : PubMed/NCBI | |
|
Karlsson R, Pedersen ED, Wang Z and Brakebusch C: Rho GTPase function in tumorigenesis. Biochim Biophys Acta. 1796:91–98. 2009.PubMed/NCBI | |
|
Royer C and Lu X: Epithelial cell polarity: A major gatekeeper against cancer? Cell Death Differ. 18:1470–1477. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Joyce JA and Pollard JW: Microenvironmental regulation of metastasis. Nat Rev Cancer. 9:239–252. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Parri M and Chiarugi P: Rac and Rho GTPases in cancer cell motility control. Cell Commun Signal. 8:23. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Mackay AR, Gomez DE, Nason AM and Thorgeirsson UP: Studies on the effects of laminin, E-8 fragment of laminin and synthetic laminin peptides PA22-2 and YIGSR on matrix metalloproteinases and tissue inhibitor of metalloproteinase expression. Lab Invest. 70:800–806. 1994.PubMed/NCBI | |
|
Zavarella S, Nakada M, Belverud S, Coniglio SJ, Chan A, Mittler MA, Schneider SJ and Symons M: Role of Rac1-regulated signaling in medulloblastoma invasion. Laboratory investigation. J Neurosurg Pediatr. 4:97–104. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Salhia B, Tran NL, Chan A, Wolf A, Nakada M, Rutka F, Ennis M, McDonough WS, Berens ME, Symons M, et al: The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol. 173:1828–1838. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR and Symons M: Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene. 24:7821–7829. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
de Lorenzo MS, Ripoll GV, Yoshiji H, Yamazaki M, Thorgeirsson UP, Alonso DF and Gomez DE: Altered tumor angiogenesis and metastasis of B16 melanoma in transgenic mice overexpressing tissue inhibitor of metalloproteinases-1. In Vivo. 17:45–50. 2003.PubMed/NCBI | |
|
Bryan BA and D'Amore PA: What tangled webs they weave: Rho-GTPase control of angiogenesis. Cell Mol Life Sci. 64:2053–2065. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Habets GG, van der Kammen RA, Stam JC, Michiels F and Collard JG: Sequence of the human invasion-inducing TIAM1 gene, its conservation in evolution and its expression in tumor cell lines of different tissue origin. Oncogene. 10:1371–1376. 1995.PubMed/NCBI | |
|
van Leeuwen FN, van der Kammen RA, Habets GG and Collard JG: Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells. Oncogene. 11:2215–2221. 1995.PubMed/NCBI | |
|
Li Z, Liu Q, Piao J, Hua F, Wang J, Jin G, Lin Z and Zhang Y: Clinicopathological implications of Tiam1 overexpression in invasive ductal carcinoma of the breast. BMC Cancer. 16:6812016. View Article : Google Scholar : PubMed/NCBI | |
|
Razidlo GL, Magnine C, Sletten AC, Hurley RM, Almada LL, Fernandez-Zapico ME, Ji B and McNiven MA: Targeting pancreatic cancer metastasis by inhibition of Vav1, a driver of tumor cell invasion. Cancer Res. 75:2907–2915. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Yang C, Liu Y, Leskow FC, Weaver VM and Kazanietz MG: Rac-GAP-dependent inhibition of breast cancer cell proliferation by {beta}2-chimerin. J Biol Chem. 280:24363–24370. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Menna PL, Skilton G, Leskow FC, Alonso DF, Gomez DE and Kazanietz MG: Inhibition of aggressiveness of metastatic mouse mammary carcinoma cells by the beta2-chimaerin GAP domain. Cancer Res. 63:2284–2291. 2003.PubMed/NCBI | |
|
Gomez DE, Armando RG and Alonso DF: AZT as a telomerase inhibitor. Front Oncol. 2:1132012. View Article : Google Scholar : PubMed/NCBI | |
|
Armando RG, Gomez DM and Gomez DE: AZT exerts its antitumoral effect by telomeric and non-telomeric effects in a mammary adenocarcinoma model. Oncol Rep. 36:2731–2736. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Qu Y, Mao M, Li X, Zhang L, Huang X, Yang C, Zhao F, Xiong Y and Mu D: Enhanced migration and CXCR4 over-expression in fibroblasts with telomerase reconstitution. Mol Cell Biochem. 313:45–52. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Yeh YM, Pan YT and Wang TC: Cdc42/Rac1 participates in the control of telomerase activity in human nasopharyngeal cancer cells. Cancer Lett. 218:207–213. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Gomez DLM, Armando RG, Cerrudo CS, Ghiringhelli PD and Gomez DE: Telomerase as a cancer target. Development of new molecules. Curr Top Med Chem. 16:2432–2440. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Fernández Larrosa PN, Ruíz Grecco M, Mengual Gómez D, Alvarado CV, Panelo LC, Rubio MF, Alonso DF, Gómez DE and Costas MA: RAC3 more than a nuclear receptor coactivator: A key inhibitor of senescence that is downregulated in aging. Cell Death Dis. 6:e19022015. View Article : Google Scholar : PubMed/NCBI | |
|
Chen PC, Peng JR, Huang L, Li WX, Wang WZ, Cui ZQ, Han H, Gong L, Xiang DP, Qiao SS, et al: Overexpression of human telomerase reverse transcriptase promotes the motility and invasiveness of HepG2 cells in vitro. Oncol Rep. 30:1157–1164. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Gómez DL, Farina HG and Gómez DE: Telomerase regulation: A key to inhibition? (Review). Int J Oncol. 43:1351–1356. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Cassimeris L: The oncoprotein 18/stathmin family of microtubule destabilizers. Curr Opin Cell Biol. 14:18–24. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Tyler JJ, Allwood EG and Ayscough KR: WASP family proteins, more than Arp2/3 activators. Biochem Soc Trans. 44:1339–1345. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Choi S and Anderson RA: IQGAP1 is a phosphoinositide effector and kinase scaffold. Adv Biol Regul. 60:29–35. 2016. View Article : Google Scholar : | |
|
Dummler B, Ohshiro K, Kumar R and Field J: Pak protein kinases and their role in cancer. Cancer Metastasis Rev. 28:51–63. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Parsons M and Adams JC: Rac regulates the interaction of fascin with protein kinase C in cell migration. J Cell Sci. 121:2805–2813. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Wei L, Surma M, Shi S, Lambert-Cheatham N and Shi J: Novel insights into the roles of Rho kinase in cancer. Arch Immunol Ther Exp (Warsz). 64:259–278. 2016. View Article : Google Scholar | |
|
Rattan S and Singh J: RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter. Am J Physiol Gastrointest Liver Physiol. 302:G664–G675. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Dawson JC, Bruche S, Spence HJ, Braga VM and Machesky LM: Mtss1 promotes cell-cell junction assembly and stability through the small GTPase Rac1. PLoS One. 7:e311412012. View Article : Google Scholar : PubMed/NCBI | |
|
Zandvakili I, Lin Y, Morris JC and Zheng Y: Rho GTPases: Anti-or pro-neoplastic targets. Oncogene. 36:3213–3222. 2017. View Article : Google Scholar | |
|
Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C and Kehrer-Sawatzki H: Where genotype is not predictive of phenotype: Towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet. 132:1077–1130. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Gao Y, Dickerson JB, Guo F, Zheng J and Zheng Y: Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA. 101:7618–7623. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Bid HK, Roberts RD, Manchanda PK and Houghton PJ: RAC1: An emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther. 12:1925–1934. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Kaneto N, Yokoyama S, Hayakawa Y, Kato S, Sakurai H and Saiki I: RAC1 inhibition as a therapeutic target for gefitinib-resistant non-small-cell lung cancer. Cancer Sci. 105:788–794. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Dokmanovic M, Wu Y, Shen Y, Chen J, Hirsch DS and Wu WJ: Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition. Cancer Biol Ther. 15:1029–1041. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Karpel-Massler G, Westhoff MA, Kast RE, Dwucet A, Karpel-Massler S, Nonnenmacher L, Siegelin MD, Wirtz CR, Debatin KM and Halatsch ME: Simultaneous interference with HER1/EGFR and RAC1 signaling drives cytostasis and suppression of survivin in human glioma cells in vitro. Neurochem Res. 42:1543–1554. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Montalvo-Ortiz BL, Castillo-Pichardo L, Hernández E, Humphries-Bickley T, De la Mota-Peynado A, Cubano LA, Vlaar CP and Dharmawardhane S: Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase. J Biol Chem. 287:13228–13238. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Cardama GA, Comin MJ, Hornos L, Gonzalez N, Defelipe L, Turjanski AG, Alonso DF, Gomez DE and Menna PL: Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anticancer Agents Med Chem. 14:840–851. 2014. View Article : Google Scholar : | |
|
Gonzalez N, Cardama GA, Comin MJ, Segatori VI, Pifano M, Alonso DF, Gomez DE and Menna PL: Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in human resistant breast cancer cells. Cell Signal. 30:154–161. 2017. View Article : Google Scholar | |
|
Felekkis KN, Narsimhan RP, Near R, Castro AF, Zheng Y, Quilliam LA and Lerner A: AND-34 activates phosphatidylinositol 3-kinase and induces anti-estrogen resistance in a SH2 and GDP exchange factor-like domain-dependent manner. Mol Cancer Res. 3:32–41. 2005.PubMed/NCBI | |
|
Cai D, Iyer A, Felekkis KN, Near RI, Luo Z, Chernoff J, Albanese C, Pestell RG and Lerner A: AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter. Cancer Res. 63:6802–6808. 2003.PubMed/NCBI | |
|
Cardama GA, Gonzalez N, Ciarlantini M, Gandolfi Donadío L, Comin MJ, Alonso DF, Menna PL and Gomez DE: Proapoptotic and antiinvasive activity of Rac1 small molecule inhibitors on malignant glioma cells. Onco Targets Ther. 7:2021–2033. 2014.PubMed/NCBI | |
|
Hwang SY, Jung JW, Jeong JS, Kim YJ, Oh ES, Kim TH, Kim JY, Cho KH and Han IO: Dominant-negative Rac increases both inherent and ionizing radiation-induced cell migration in C6 rat glioma cells. Int J Cancer. 118:2056–2063. 2006. View Article : Google Scholar | |
|
Delmas C, Heliez C, Cohen-Jonathan E, End D, Bonnet J, Favre G and Toulas C: Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation. Int J Cancer. 100:43–48. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Zhai GG, Malhotra R, Delaney M, Latham D, Nestler U, Zhang M, Mukherjee N, Song Q, Robe P and Chakravarti A: Radiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway. J Neurooncol. 76:227–237. 2006. View Article : Google Scholar | |
|
Florian MC, Dörr K, Niebel A, Daria D, Schrezenmeier H, Rojewski M, Filippi MD, Hasenberg A, Gunzer M, Scharffetter-Kochanek K, et al: Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell. 10:520–530. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Hong L, Kenney SR, Phillips GK, Simpson D, Schroeder CE, Nöth J, Romero E, Swanson S, Waller A, Strouse JJ, et al: Characterization of a Cdc42 protein inhibitor and its use as a molecular probe. J Biol Chem. 288:8531–8543. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Friesland A, Zhao Y, Chen YH, Wang L, Zhou H and Lu Q: Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility. Proc Natl Acad Sci USA. 110:1261–1266. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Shang X, Marchioni F, Sipes N, Evelyn CR, Jerabek-Willemsen M, Duhr S, Seibel W, Wortman M and Zheng Y: Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases. Chem Biol. 19:699–710. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Shutes A, Onesto C, Picard V, Leblond B, Schweighoffer F and Der CJ: Specificity and mechanism of action of EHT 1864, a novel small molecule inhibitor of Rac family small GTPases. J Biol Chem. 282:35666–35678. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Arnst JL, Hein AL, Taylor MA, Palermo NY, Contreras JI, Sonawane YA, Wahl AO, Ouellette MM, Natarajan A and Yan Y: Discovery and characterization of small molecule Rac1 inhibitors. Oncotarget. 8:34586–34600. 2017.PubMed/NCBI | |
|
Mazieres J, Pradines A and Favre G: Perspectives on farnesyl transferase inhibitors in cancer therapy. Cancer Lett. 206:159–167. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Chan KK, Oza AM and Siu LL: The statins as anticancer agents. Clin Cancer Res. 9:10–19. 2003.PubMed/NCBI | |
|
Farina HG, Bublik DR, Alonso DF and Gomez DE: Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells. Clin Exp Metastasis. 19:551–559. 2002. View Article : Google Scholar : PubMed/NCBI | |
|
Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, Takai Y, Williams CL, Liao JK and Shimokawa H: Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol. 33:1591–1600. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Michaelson D, Abidi W, Guardavaccaro D, Zhou M, Ahearn I, Pagano M and Philips MR: Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division. J Cell Biol. 181:485–496. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Navarro-Lérida I, Pellinen T, Sanchez SA, Guadamillas MC, Wang Y, Mirtti T, Calvo E and Del Pozo MA: Rac1 nucleocytoplasmic shuttling drives nuclear shape changes and tumor invasion. Dev Cell. 32:318–334. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Mendoza-Catalán MA, Cristóbal-Mondragón GR, Adame-Gómez J, del Valle-Flores HN, Coppe JF, Sierra-López L, Romero-Hernández MA, del Carmen Alarcón-Romero L, Illades-Aguiar B and Castañeda-Saucedo E: Nuclear expression of Rac1 in cervical premalignant lesions and cervical cancer cells. BMC Cancer. 12:116. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Lu J, Chan L, Fiji HDG, Dahl R, Kwon O and Tamanoi F: In vivo antitumor effect of a novel inhibitor of protein geranylgeranyltransferase-I. Mol Cancer Ther. 8:1218–1226. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Zimonjic DB, Chan LN, Tripathi V, Lu J, Kwon O, Popescu NC, Lowy DR and Tamanoi F: In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells. BMC Cancer. 13:198. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Berndt N, Hamilton AD and Sebti SM: Targeting protein prenylation for cancer therapy. Nat Rev Cancer. 11:775–791. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Draper JM, Xia Z and Smith CD: Cellular palmitoylation and trafficking of lipidated peptides. J Lipid Res. 48:1873–1884. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Nagumo H, Sasaki Y, Ono Y, Okamoto H, Seto M and Takuwa Y: Rho kinase inhibitor HA-1077 prevents Rho-mediated myosin phosphatase inhibition in smooth muscle cells. Am J Physiol Cell Physiol. 278:C57–C65. 2000.PubMed/NCBI | |
|
Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, et al: Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 389:990–994. 1997. View Article : Google Scholar : PubMed/NCBI | |
|
Kale VP, Hengst JA, Desai DH, Amin SG and Yun JK: The regulatory roles of ROCK and MRCK kinases in the plasticity of cancer cell migration. Cancer Lett. 361:185–196. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
James SE, Burden H, Burgess R, Xie Y, Yang T, Massa SM, Longo FM and Lu Q: Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants. Neurotoxicology. 29:605–612. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Dong M, Yan BP, Liao JK, Lam YY, Yip GWK and Yu CM: Rho-kinase inhibition: A novel therapeutic target for the treatment of cardiovascular diseases. Drug Discov Today. 15:622–629. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Fritz G and Kaina B: Rho GTPases: Promising cellular targets for novel anticancer drugs. Curr Cancer Drug Targets. 6:1–14. 2006.PubMed/NCBI | |
|
Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR and Cohen P: The selectivity of protein kinase inhibitors: A further update. Biochem J. 408:297–315. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Boerma M, Fu Q, Wang J, Loose DS, Bartolozzi A, Ellis JL, McGonigle S, Paradise E, Sweetnam P, Fink LM, et al: Comparative gene expression profiling in three primary human cell lines after treatment with a novel inhibitor of Rho kinase or atorvastatin. Blood Coagul Fibrinolysis. 19:709–718. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Sadok A, McCarthy A, Caldwell J, Collins I, Garrett MD, Yeo M, Hooper S, Sahai E, Kuemper S, Mardakheh FK, et al: Rho kinase inhibitors block melanoma cell migration and inhibit metastasis. Cancer Res. 75:2272–2284. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, et al: CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 111:1133–1145. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Menna PL, Parera RL, Cardama GA, Alonso DF, Gomez DE and Farina HG: Enhanced cytostatic activity of statins in mouse mammary carcinoma cells overexpressing β2-chimaerin. Mol Med Rep. 2:97–102. 2009.PubMed/NCBI | |
|
Becker MS, Müller PM, Bajorat J, Schroeder A, Giaisi M, Amin E, Ahmadian MR, Rocks O, Köhler R, Krammer PH, et al: The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration. Oncotarget. 7:51908–51921. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Dent P, Curiel DT, Fisher PB and Grant S: Synergistic combinations of signaling pathway inhibitors: Mechanisms for improved cancer therapy. Drug Resist Updat. 12:65–73. 2009. View Article : Google Scholar : PubMed/NCBI |
