Proapoptotic and Antiinvasive Activity of Rac1 Small Molecule Inhibitors on Malignant Glioma Cells

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2014 Nov 8

PMID 25378937

Citations 22

Authors

Georgina A Cardama

Nazareno Gonzalez

Matias Ciarlantini

Lucia Gandolfi Donadio

Maria Julieta Comin

Daniel F Alonso

Pablo Lorenzano Menna

Daniel E Gomez

Affiliations

Soon will be listed here.

Abstract

Malignant gliomas are characterized by an intrinsic ability to invade diffusely throughout the normal brain tissue. This feature contributes mainly to the failure of existing therapies. Deregulation of small GTPases signaling, in particular Rac1 activity, plays a key role in the invasive phenotype of gliomas. Here we report the effect of ZINC69391, a specific Rac1 inhibitor developed by our group, on human glioma cell lines LN229 and U-87 MG. ZINC69391 is able to interfere with the interaction of Rac1 with Dock180, a relevant Rac1 activator in glioma invasion, and to reduce Rac1-GTP levels. The kinase Pak1, a downstream effector of Dock180-Rac1 signaling, was also downregulated upon ZINC69391 treatment. ZINC69391 reduced cell proliferation, arrested cells in G1 phase, and triggered apoptosis in glioma cells. Importantly, ZINC69391 dramatically affected cell migration and invasion in vitro, interfering with actin cytoskeleton dynamics. We also evaluated the effect of analog 1A-116, a compound derived from ZINC69391 structure. 1A-116 showed an improved antiproliferative and antiinvasive activity on glioma cells. These findings encourage further preclinical testing in clinically relevant animal models.

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References

Ye D, Field J . PAK signaling in cancer. Cell Logist. 2012; 2(2):105-116. PMC: 3490961. DOI: 10.4161/cl.21882. View

Vader P, van der Meel R, Symons M, Fens M, Pieters E, Wilschut K . Examining the role of Rac1 in tumor angiogenesis and growth: a clinically relevant RNAi-mediated approach. Angiogenesis. 2011; 14(4):457-66. DOI: 10.1007/s10456-011-9229-x. View

Hirata E, Yukinaga H, Kamioka Y, Arakawa Y, Miyamoto S, Okada T . In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion. J Cell Sci. 2012; 125(Pt 4):858-68. DOI: 10.1242/jcs.089995. View

Etienne-Manneville S, Hall A . Rho GTPases in cell biology. Nature. 2002; 420(6916):629-35. DOI: 10.1038/nature01148. View

Fritz G, Just I, Kaina B . Rho GTPases are over-expressed in human tumors. Int J Cancer. 1999; 81(5):682-7. DOI: 10.1002/(sici)1097-0215(19990531)81:5<682::aid-ijc2>3.0.co;2-b. View

Rossman K, Der C, Sondek J . GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol. 2005; 6(2):167-80. DOI: 10.1038/nrm1587. View

Yoon C, Hyun K, Kim R, Lee H, Lim E, Chung H . The small GTPase Rac1 is involved in the maintenance of stemness and malignancies in glioma stem-like cells. FEBS Lett. 2011; 585(14):2331-8. DOI: 10.1016/j.febslet.2011.05.070. View

Jarzynka M, Hu B, Hui K, Bar-Joseph I, Gu W, Hirose T . ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion. Cancer Res. 2007; 67(15):7203-11. PMC: 2867339. DOI: 10.1158/0008-5472.CAN-07-0473. View

Vigil D, Cherfils J, Rossman K, Der C . Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat Rev Cancer. 2010; 10(12):842-57. PMC: 3124093. DOI: 10.1038/nrc2960. View

10.

Karpel-Massler G, Westhoff M, Zhou S, Nonnenmacher L, Dwucet A, Kast R . Combined inhibition of HER1/EGFR and RAC1 results in a synergistic antiproliferative effect on established and primary cultured human glioblastoma cells. Mol Cancer Ther. 2013; 12(9):1783-95. DOI: 10.1158/1535-7163.MCT-13-0052. View

11.

Gao Y, Xing J, Streuli M, Leto T, Zheng Y . Trp(56) of rac1 specifies interaction with a subset of guanine nucleotide exchange factors. J Biol Chem. 2001; 276(50):47530-41. DOI: 10.1074/jbc.M108865200. View

12.

Pille J, Denoyelle C, Varet J, Bertrand J, Soria J, Opolon P . Anti-RhoA and anti-RhoC siRNAs inhibit the proliferation and invasiveness of MDA-MB-231 breast cancer cells in vitro and in vivo. Mol Ther. 2005; 11(2):267-74. DOI: 10.1016/j.ymthe.2004.08.029. View

13.

Feng H, Hu B, Vuori K, Sarkaria J, Furnari F, Cavenee W . EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. Oncogene. 2013; 33(19):2504-12. PMC: 3883905. DOI: 10.1038/onc.2013.198. View

14.

Manser E, Leung T, Salihuddin H, Zhao Z, Lim L . A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994; 367(6458):40-6. DOI: 10.1038/367040a0. View

15.

Cardama G, Comin M, Hornos L, Gonzalez N, Defelipe L, Turjanski A . Preclinical development of novel Rac1-GEF signaling inhibitors using a rational design approach in highly aggressive breast cancer cell lines. Anticancer Agents Med Chem. 2013; 14(6):840-51. PMC: 4104455. DOI: 10.2174/18715206113136660334. View

16.

Ong C, Jubb A, Haverty P, Zhou W, Tran V, Truong T . Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc Natl Acad Sci U S A. 2011; 108(17):7177-82. PMC: 3084065. DOI: 10.1073/pnas.1103350108. View

17.

Maher E, Furnari F, Bachoo R, Rowitch D, Louis D, Cavenee W . Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001; 15(11):1311-33. DOI: 10.1101/gad.891601. View

18.

Chan A, Coniglio S, Chuang Y, Michaelson D, Knaus U, Philips M . Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene. 2005; 24(53):7821-9. DOI: 10.1038/sj.onc.1208909. View

19.

Fortin Ensign S, Mathews I, Symons M, Berens M, Tran N . Implications of Rho GTPase Signaling in Glioma Cell Invasion and Tumor Progression. Front Oncol. 2013; 3:241. PMC: 3790103. DOI: 10.3389/fonc.2013.00241. View

20.

Krauthammer M, Kong Y, Ha B, Evans P, Bacchiocchi A, McCusker J . Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 2012; 44(9):1006-14. PMC: 3432702. DOI: 10.1038/ng.2359. View