Increased Rac1b Expression Sustains Colorectal Tumor Cell Survival

The small GTPase Rac1 can stimulate various signaling pathways that contribute to cell transformation. In particular, the activation of the NFκB transcription factor initiates an antiapoptotic response and promotes cell cycle progression through increased cyclin D1 expression. As a potential oncogenic mechanism to up-regulate this pathway, the overexpression of the Rac1b splicing variant was reported in some colorectal tumors. Rac1b exists predominantly in the active GTP-bound state and selectively promotes the pathway leading to NFκB activation. Here, we studied the role of endogenous Rac1b in colorectal cancer cells. We found that depletion of Rac1b by small interfering RNAs inhibited endogenous NFκB activation and reduced cell viability to 50% within 48 hours. This reduction was due to increased apoptosis, although a reduced G1-S progression rate was also observed. These data show, for the first time, that colorectal cells expressing alternative spliced Rac1b also depend on Rac1b signaling to sustain their survival. (Mol Cancer Res 2008;6(7):1178–84)

[1]  A. Sweet-Cordero,et al.  Requirement for Rac1 in a K-ras induced lung cancer in the mouse. , 2007, Cancer research.

[2]  B. Bapat,et al.  Activation of tumor-specific splice variant Rac1b by dishevelled promotes canonical Wnt signaling and decreased adhesion of colorectal cancer cells. , 2007, Cancer research.

[3]  L. Johnson,et al.  Rac1 mediates intestinal epithelial cell apoptosis via JNK. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[4]  Y. Tsao,et al.  Activation of mitogen-activated protein kinases is essential for hydrogen peroxide -induced apoptosis in retinal pigment epithelial cells , 2006, Apoptosis.

[5]  P. Jordan,et al.  Rac1, but Not Rac1B, Stimulates RelB-mediated Gene Transcription in Colorectal Cancer Cells* , 2006, Journal of Biological Chemistry.

[6]  A. Ridley,et al.  Rho GTPases and cell cycle control , 2006, Growth factors.

[7]  Alan Hall,et al.  Rho GTPases: biochemistry and biology. , 2005, Annual review of cell and developmental biology.

[8]  D. Albertson,et al.  Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability , 2005, Nature.

[9]  P. Jordan,et al.  Expression of Rac1b stimulates NF-kappaB-mediated cell survival and G1/S progression. , 2005, Experimental cell research.

[10]  Vani Santosh,et al.  Differential protein expression in human gliomas and molecular insights , 2005, Proteomics.

[11]  C. Der,et al.  GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors , 2005, Nature Reviews Molecular Cell Biology.

[12]  E. Lengyel,et al.  Rac1b, a tumor associated, constitutively active Rac1 splice variant, promotes cellular transformation , 2004, Oncogene.

[13]  W. Greene,et al.  Shaping the nuclear action of NF-κB , 2004, Nature Reviews Molecular Cell Biology.

[14]  Krister Wennerberg,et al.  Rho-family GTPases: it's not only Rac and Rho (and I like it) , 2004, Journal of Cell Science.

[15]  Radovan Dvorsky,et al.  Alternative Splicing of Rac1 Generates Rac1b, a Self-activating GTPase* , 2004, Journal of Biological Chemistry.

[16]  John G. Collard,et al.  Tumor-related Alternatively Spliced Rac1b Is Not Regulated by Rho-GDP Dissociation Inhibitors and Exhibits Selective Downstream Signaling* , 2003, Journal of Biological Chemistry.

[17]  C. Moskaluk,et al.  RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. , 2002, Cancer research.

[18]  John G. Collard,et al.  Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours , 2002, Nature.

[19]  E. Sahai,et al.  RHO–GTPases and cancer , 2002, Nature Reviews Cancer.

[20]  S. Pervaiz,et al.  Activation of the RacGTPase inhibits apoptosis in human tumor cells , 2001, Oncogene.

[21]  C. Woo,et al.  Implication of the small GTPase Rac1 in the apoptosis induced by UV in Rat-2 fibroblasts. , 2001, Biochemical and biophysical research communications.

[22]  M. Symons,et al.  The Small GTPase Rac Suppresses Apoptosis Caused by Serum Deprivation in Fibroblasts , 2001, Molecular medicine.

[23]  S. Scherer,et al.  Small GTPase Rac1: structure, localization, and expression of the human gene. , 2000, Biochemical and biophysical research communications.

[24]  T. Zwaka,et al.  Tiam1 mutations in human renal‐cell carcinomas , 2000, International journal of cancer.

[25]  E. Lengyel,et al.  Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b , 2000, Oncogene.

[26]  P. Jordan,et al.  Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors , 1999, Oncogene.

[27]  C. Der,et al.  Integration of Rac-dependent Regulation of Cyclin D1 Transcription through a Nuclear Factor-κB-dependent Pathway* , 1999, The Journal of Biological Chemistry.

[28]  D. Bar-Sagi,et al.  Suppression of Ras-Induced Apoptosis by the Rac GTPase , 1999, Molecular and Cellular Biology.

[29]  Chris Albanese,et al.  NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1 , 1999, Molecular and Cellular Biology.

[30]  B. Kaina,et al.  Rho GTPases are over‐expressed in human tumors , 1999, International journal of cancer.

[31]  Claus Scheidereit,et al.  NF-κB Function in Growth Control: Regulation of Cyclin D1 Expression and G0/G1-to-S-Phase Transition , 1999, Molecular and Cellular Biology.

[32]  T. M. Johnson,et al.  Rac1 is required for cell proliferation and G2/M progression. , 1997, The Biochemical journal.

[33]  R. Bravo,et al.  Activation of the nuclear factor-kappaB by Rho, CDC42, and Rac-1 proteins. , 1997, Genes & development.

[34]  C. Der,et al.  Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation , 1995, Molecular and cellular biology.

[35]  A. Ashworth,et al.  An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1 , 1995, Science.

[36]  F. McCormick,et al.  An essential role for Rac in Ras transformation , 1995, Nature.

[37]  W C Greene,et al.  NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. , 1993, Science.

[38]  G. Franzoso,et al.  Mutual regulation of the transcriptional activator NF-kappa B and its inhibitor, I kappa B-alpha. , 1993, Proceedings of the National Academy of Sciences of the United States of America.