Rho GTPases in transformation and metastasis

CRC Oncogene and Signal Transduction Group, University College London, UK.
Advances in Cancer Research (Impact Factor: 5.32). 02/2002; 84:57-80. DOI: 10.1016/S0065-230X(02)84003-9
Source: PubMed


During the development and progression of human cancer, cells undergo numerous changes in morphology, proliferation, and transcriptional profile. Over the past couple of decades there have been intense efforts to understand the molecular mechanisms involved, and members of the Ras superfamily of small GTPases have emerged as important players. Mutated versions of the Ras genes were first identified in human cancers some 20 years ago, but more recently, the Rho branch of the family has been receiving increased attention. In addition to the experimental evidence implicating Rho GTPase signaling in promoting malignant transformation, genetic analysis of human cancers has now revealed a few examples of direct alterations in the genes encoding regulators of Rho GTPases. In this review, we discuss the evidence implicating Rho GTPases in transformation and metastasis, as well as the progress made toward identifying their biochemical mechanism of action.

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    • "These could include some genes which are potentially involved in invadopodia formation. It has been reported that regulation of the actin cytoskeleton is essential for invadopodia formation leading to invasion and metastasis of cancer cells by promoting a variety of cellular processes such as changes in morphology, motility and adhesion (Clark et al., 2000; Jaffe and Hall, 2002). We thus chose vimentin and plectin which meet this criterion from the up-regulated genes in KK-47HM4 cells. "
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    ABSTRACT: To investigate the molecular mechanisms of cancer metastasis, we have isolated a high-metastatic bladder cancer cell subpopulation from a low-metastatic cell line by using an in vivo selection system. Cells in the subpopulation showed a high ability to form invadopodia, the filamentous actin (F-actin)-based membrane protrusions that play an essential role in cancer cell invasion. Analysis of the gene expression profile revealed that the expression of an intermediate filament (IF) protein, vimentin and a cytoskeletal linker protein, plectin was up-regulated in the high-metastatic subpopulation compared with the low metastatic cell line. Here we report a novel role of vimentin IF and plectin in metastasis. In invasive bladder cancer cells, the vimentin IF-plectin-invadopodia F-actin link was formed. Disruption of this link severely impaired invadopodia formation, reducing the capacities of extracellular matrix degradation, transendothelial migration and metastasis. In addition, the vimentin assembly into the filaments was required for invadopodia formation. Our results suggest that plectin anchoring invadopodia to vimentin IF scaffolds and stabilizes invadopodia, which is a critical molecular process for cancer cell invasion and extravasation for metastasis.
    European journal of cell biology 04/2014; 93(4). DOI:10.1016/j.ejcb.2014.03.002 · 3.83 Impact Factor
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    • "This small GTPase acts as a signaling switch, that is implicated in the regulation of a variety of molecular pathways by cycling between an active GTP and inactive GDP-bound state (Prendergast, 2001). Unlike other RHO GTPases, RHOB participates in endosome trafficking (Jaffe and Hall, 2002). Consistent with this, RHOB displays a unique pattern of cellular distribution that contributes to the cytoplasm to membrane targeting of a variety of receptors and signaling molecules (Jaffe and Hall, 2005). "
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    ABSTRACT: Lung adenocarcinoma (ADC) is the most common lung cancer subtype and presents a high mortality rate. Clinical recurrence is often associated with the emergence of metastasis and treatment resistance. The purpose of this study was to identify genes with high prometastatic activity which could potentially account for treatment resistance. Global transcriptomic profiling was performed by robust microarray analysis in highly metastatic subpopulations. Extensive in vitro and in vivo functional studies were achieved by overexpression and by silencing gene expression. We identified the small GTPase RHOB as a gene that promotes early and late stages of metastasis in ADC. Gene silencing of RHOB prevented metastatic activity in a systemic murine model of bone metastasis. These effects were highly dependent on tumor-host interactions. Clinical analysis revealed a marked association between high RHOB levels and poor survival. Consistently, high RHOB levels promote metastasis progression, taxane-chemoresistance, and contribute to the survival advantage to γ-irradiation. We postulate that RHOB belongs to a novel class of "genes of recurrence" that have a dual role in metastasis and treatment resistance.
    Molecular oncology 11/2013; 8(2). DOI:10.1016/j.molonc.2013.11.001 · 5.33 Impact Factor
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    • "GGTase-I catalyzes the geranylgeranylation of proteins containing the CAAL motif (C is cysteine, A is aliphatic amino acid and L is leucine) at their C-termini. Many of the proteins that are modified by GGTase-I are members of the Ras superfamily of GTPases, including RhoA, Rac, and Cdc42, which play important roles in human cancer [5-8]. It has been shown that slowed growth of mouse embryonic fibroblasts (MEFs) derived from cells defective in GGTase-I was reversed by expressing mutant forms of both RhoA and Cdc42 that can bypass the geranylgeranylation requirement [4], suggesting that the effects of GGTase-I inhibition are largely mediated by these Rho family proteins. "
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    ABSTRACT: Background Lung cancer is the leading cause of cancer-related mortality. Therapies against non-small cell lung cancer (NSCLC) are particularly needed, as this type of cancer is relatively insensitive to chemotherapy and radiation therapy. We recently identified GGTI compounds that are designed to block geranylgeranylation and membrane association of signaling proteins including the Rho family G-proteins. One of the GGTIs is P61A6 which inhibits proliferation of human cancer cells, causes cell cycle effects with G1 accumulation and exhibits tumor-suppressing effects with human pancreatic cancer xenografts. In this paper, we investigated effects of P61A6 on non-small cell lung cancer (NSCLC) cells in vitro and in vivo. Methods Three non-small cell lung cancer cell lines were used to test the ability of P61A6 to inhibit cell proliferation. Further characterization involved analyses of geranylgeranylation, membrane association and activation of RhoA, and anchorage-dependent and –independent growth, as well as cell cycle effects and examination of cell cycle regulators. We also generated stable cells expressing RhoA-F, which bypasses the geranylgeranylation requirement of wild type RhoA, and examined whether the proliferation inhibition by P61A6 is suppressed in these cells. Tumor xenografts of NSCLC cells growing in nude mice were also used to test P61A6’s tumor-suppressing ability. Results P61A6 was shown to inhibit proliferation of NSCLC lines H358, H23 and H1507. Detailed analysis of P61A6 effects on H358 cells showed that P61A6 inhibited geranylgeranylation, membrane association of RhoA and caused G1 accumulation associated with decreased cyclin D1/2. The effects of P61A6 to inhibit proliferation could mainly be ascribed to RhoA, as expression of the RhoA-F geranylgeranylation bypass mutant rendered the cells resistant to inhibition by P61A6. We also found that P61A6 treatment of H358 tumor xenografts growing in nude mice reduced their growth as well as the membrane association of RhoA in the tumors. Conclusion Thus, P61A6 inhibits proliferation of NSCLC cells and causes G1 accumulation associated with decreased cyclin D1/2. The result with the RhoA-F mutant suggests that the effect of P61A6 to inhibit proliferation is mainly through the inhibition of RhoA. P61A6 also shows efficacy to inhibit growth of xenograft tumor.
    BMC Cancer 04/2013; 13(1):198. DOI:10.1186/1471-2407-13-198 · 3.36 Impact Factor
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