Rho蛋白在肿瘤发生发展中的作用

Rho蛋白是参与细胞内信号转导的重要蛋白,Rho家族成员及其各自的已知下游效应分子参与调节细胞的增殖、基因表达,同时是改变细胞骨架组装、调控细胞迁移进而参与肿瘤发生发展的关键因子,具有潜在而重要的临床应用价值。     

Rho GTPases in human carcinogenesis: a tale of excess

Rho GTPases are proteins that in response to diverse stimuli control key signaling and structural aspects of the cell. Although early studies had proposed a role for Rho GTPases in cellular transformation, this effect was underestimated by the fact that no genetic mutations affecting Rho-encoding genes was found in human tumors. However, in recent years a high incidence of overexpression of different members of the family of Rho GTPases in human tumors has been detected which is leading to a great interest in the cellular effects elicited by these oncoproteins. As well, the characterization of downstream effectors and upstream regulators of Rho GTPases provides crucial clues on the specific cellular effects that permit aberrant cellular growth and tumorigenesis. A direct link between the functions of some of these signaling elements and regulation of the cell cycle, cytoskeletal rearrangements and cell adhesion has been observed in distinct types of human tumors. Provided this information, a number of drugs that affect Rho signaling at different levels have been described with promisingin vivo antitumoral activity. In this review, the current evidence of dysregulation of Rho signaling in human tumors is assembled.     

Inflammatory breast cancer: Relationship between growth factor signaling and motility in aggressive cancers

A variety of phenotypic characteristics are required for a cancer cell to successfully complete the metastatic cascade. Acquisition of a motile and invasive phenotype is one requirement for a cell to become metastatically competent. The Rho (Ras homology) GTPases are a subfamily of small GTP-binding proteins, which are related to the Ras oncogene. All aspects of cellular motility and invasion are controlled by the Rho GTPases and are closely linked to signals from the extracellular environment, particularly in response to growth factors. Dysregulation of Rho activation through aberrant growth-factor signaling, loss of function of key Rho-regulatory proteins or overexpression of Rho mRNA could result in increased Rho activity and cellular motility. Therefore, the importance of the Rho GTPases in the progression of aggressive cancers, is becoming more appreciated.     

Integrin-mediated function of Rab GTPases in cancer progression

The RAS (rat sarcoma) superfamily of small GTPases is broadly subdivided into five groups: Ras, Rho, Rab, Ran, and Arf. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, proliferation, vesicle transport, nuclear assembly, and cytoskeleton formation. However, some Rab proteins have been reported to be necessary for the adhesion and migration of cancer cells. Although Ras and Rho family members have been strongly implicated in cancer progression, knowledge of Rabs action in this regard is limited. Some reports have also linked Rab GTPases with cancer cell migration and invasiveness. This review discusses the implications of the involvement of Rabs in malignant transformation and cancer therapy through integrin-mediated signaling events, with particular emphasis on breast cancer.     

HMG-CoA reductase inhibitors (statins) as anticancer drugs (review)

Apart from their lipid lowering activity, HMG-CoA reductase inhibitors (statins) impair numerous cellular functions associated with metastasis, e.g. gene expression, angiogenesis, cell adhesion, cell motility and invasiveness. Furthermore, statins have impact on apoptotic cell death and modulate cellular susceptibility to cell killing by anticancer drugs and ionizing radiation. Part of the effects provoked by statins are due to the inhibition of the prenylation of low molecular weight GTPases, in particular Ras and Rho, which play key roles in signaling evoked by stimulation of cell surface receptors. C-terminal lipid modification of Ras/Rho GTPases is essential for their correct intracellular localization and function. By depletion of the cellular pool of isoprene precursor molecules, statins reduce the level of membrane-bound active Ras/Rho proteins, thereby impairing corresponding functions. Since broad clinical experience already exists for statins, their incorporation into established tumor-therapeutic regimens would be realizable in a rather short period of time. Here, data available at present arguing for the usefulness of statins in anticancer therapy are summarized and discussed.     

Rho, Rac, Pak and angiogenesis: old roles and newly identified responsibilities in endothelial cells

Angiogenesis-the develoment of microvasculature-requires, in part, directed endothelial cell motility and responsiveness to external signals. Several of the proteins, which modulate and/or direct endothelial cell motility and morphology in angiogenesis are the Rho GTPases (Rho, Rac, and Cdc42) and Pak (a downstream effector of Rac and Cdc42). Previously, overexpression and activation of Rho GTPases and Pak had been implicated in the development of cancer, through their roles in cancer cell transformation, stimulation of proliferation, inhibition of apoptosis, and migration. Yet regardless of the transformed status of cells within a tumor, without a blood supply most tumors cannot grow larger than 1-2 mm. The blood supply in tumors is provided by capillaries formed of endothelial cells in a process called angiogenesis. Consequently, there is enormous interest in the role of the wild type endothelial cells-and the signaling mechanisms required to support angiogenesis and subsequent growth of metastatic and aggressive cancers. Recent work has begun to uncover the roles of the Rho GTPases and Pak in the regulation of normal endothelial cell function. This review will discuss the current literature regarding the roles of Rho and Rac, and the Rac effector-Pak, in endothelial cells, and we will propose new avenues of research for interaction of the AGC kinase-PKG, with the Rho GTPases and Pak in the cell motility and cell morphology of endothelial cells.     

Rho GTPases as Key Transducers of Proliferative Signals in G1 Cell Cycle Regulation

Mitogenic growth factor- and integrin-dependent signaling pathways cooperate to control the proliferation of nontransformed cells. As integral mediators of these networks, the Rho family of GTPases play a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 expression, as well as the levels of the cyclin-dependent kinase inhibitors p21cip1 and p27kip1. Such dual control of both the critical positive and negative regulators of G1 progression make the Rho GTPases prime candidates to target the autonomous proliferation which typifies cancer cells. Cyclin D1 has been identified as an important oncogene and the cdk inhibitors as tumor suppressors in human breast carcinogenesis. Evidence pointing to the potential role of Rho-dependent pathways and their interaction with oncogenic Ras in contributing to such cell cycle abnormalities that characterize human breast cancer is also presented.     

Molecular Basis for Rho GTPase Signaling Specificity

There is now considerable evidence for the involvement of aberrant Rho GTPase activation in breast cancer development. Like Ras, Rho GTPases function as signaling nodes regulated by diverse extracellular stimuli. Rho GTPase activation is facilitated by multiple regulatory proteins, in particular guanine nucleotide exchange factors (GEFs) such as Dbl family proteins. Activated Rho GTPases in turn interact with and regulate a spectrum of functionally diverse downstream effectors, initiating a network of cytoplasmic and nuclear signaling cascades. Thus, Rho GTPases represent points of signaling convergence as well as relay switches that disseminate signaling divergence. In this review, we highlight issues relating to the structural basis by which Dbl family GEFs facilitate signaling convergence and Rho GTPase activation, and how Rho GTPases promote signal dissemination through downstream effectors.     

Rho GTPases in primary brain tumor malignancy and invasion

Gliomas are the most common type of malignant primary brain tumor in humans, accounting for 80?% of malignant cases. Expression and activity of Rho GTPases, which coordinate several cellular processes including cell-cycle progression and cell migration, are commonly altered in many types of primary brain tumor. Here we review the suggested effects of deregulated Rho GTPase signaling on brain tumor malignancy, highlighting the controversy in the field. For instance, whereas expression of RhoA and RhoB has been found to be significantly reduced in astrocytic tumors, other studies have reported Rho-dependent LPA-induced migration in glioma cells. Moreover, whereas the Rac1 expression level has been found to be reduced in astrocytic tumor, it was overexpressed and induced invasion in medulloblastoma tumors. In addition to the Rho GTPases themselves, several of their downstream effectors (including ROCK, mDia, and N-WASP) and upstream regulators (including GEFs, GAPs, PI3K, and PTEN) have also been implicated in primary brain tumors.     

Rho Proteins and Cancer

The Rho family of GTPases has been intensively studied for their roles in signal transduction processes leading to cytoskeletal-dependent responses, including cell migration and phagocytosis. In addition, they are important regulators of cell cycle progression and affect the expression of a number of genes, including those for matrix-degrading proteases implicated in cancer invasion. So far, the expression of some Rho family members has been found to be increased in some human cancers, and some cancer-associated mutations in Rho family regulators have been characterized. This makes Rho protein signalling pathways attractive targets for cancer therapy. However, there is little evidence so far from animal studies to define if and how Rho proteins contribute to cancer cell proliferation, survival, invasion and metastasis.     

Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch

The fragile histidine triad (FHIT) gene has been shown to function as a tumor suppressor gene in vitro and in vivo. However, the mechanism of its action is still largely unknown. To elucidate the molecular mechanism and biological pathway in FHIT-mediated tumor suppression, we used a complementary gene and protein expression profiling with DNA microarray and ProteinChip technologies to quantitatively monitor cellular changes in gene and protein expression and discover the molecular targets of FHIT in non-small cell lung carcinoma (NSCLC) cells. The Ras/Rho signaling pathway was identified as one of the unique biological pathways associated with FHIT activity. A significantly down-regulated expression of genes and proteins of multiple key components in the Ras/Rho GTPases molecular switch, including Ran, Rab, Rac, Rap, and Ral, was observed on gene and protein expression profiles and further validated by Western blot analysis. Ectopic activation of FHIT in FHIT-deficient H1299 cells also significantly reduced the invasive potential of tumor cells by down-regulating expression of RhoC, a potential marker of tumor cell invasion and metastases. A simultaneous knockdown of the expression of several key Ras/Rho signaling molecules using gene-specific small interfering RNAs (RHO-siRNA) targeting selected Rab11, Rac1, and Rap1 genes significantly inhibited tumor cell growth and induced apoptosis in NSCLC cells in vitro, and a local injection of RHO-siRNAs complexed with N-[1-(2,3-dioleoyloxyl)propyl]-N,N,N-trimethylammoniummethyl sulfate:cholesterol nanoparticles inhibited tumor growth in A549 tumor xenografts in mice, mimicking the AdFHIT-mediated tumor-suppressing effect. These results suggest a new role of FHIT in down-regulating the Ras/Rho GTPase-associated oncogenic signaling pathway.     

Recent advances in understanding the antineoplastic mechanisms of farnesyltransferase inhibitors

Farnesyltransferase (FTase) inhibitors (FTI) have broad antineoplastic actions targeting both cancer cells and mesenchymal cells involved in tumor angiogenesis. The small GTPases H-Ras, Rheb, and RhoB and the centromere proteins CENP-E and CENP-F are relevant targets of farnesylation inhibition; however, their relative importance in the antineoplastic effect of FTIs may vary in different cell types at different stages of the cell cycle and at different stages in oncogenesis. Three recent studies argue that Ras-independent and perhaps even FTase-independent properties are important to the antineoplastic action of this class of drugs. In mice, genetic ablation of FTase does not abolish the oncogenic activity of Ras, limiting the original conception of FTIs as an effective means to target Ras in cancer cells. FTase may not be the sole molecular target of these agents, and one study has suggested that FTIs act by targeting geranylgeranyl transferase II. Lastly, we have obtained evidence that induction of reactive oxygen species and reactive oxygen species-mediated DNA damage by FTIs may be critical for their antineoplastic action as a class. Together, these findings may alter thinking about how to apply FTIs in the clinic.     

Regulation of cancer cell motility through actin reorganization

Cell migration is a critical step in tumor invasion and metastasis, and regulation of this process will lead to appropriate therapies for treating cancer. Cancer cells migrate in various ways, according to cell type and degree of differentiation. The different types of cell migration are regulated by different mechanisms. Reorganization of the actin cytoskeleton is the primary mechanism of cell motility and is essential for most types of cell migration. Actin reorganization is regulated by Rho family small GTPases such as Rho, Rac, and Cdc42. These small GTPases transmit extracellular chemotactic signals to downstream effectors. Of these downstream effectors, Wiskott-Aldrich syndrome protein (WASP) family proteins are key regulators of cell migration. Activated WASP family proteins induce the formation of protrusive membrane structures involved in cell migration and degradation of the extracellular matrix. Inhibition of Rho family small GTPase signaling suppresses the migration and invasion of cancer cells. Thus, control of cell migration via the actin cytoskeleton provides the possibility of regulating cancer cell invasion and metastasis.     

Cortactin: coupling membrane dynamics to cortical actin assembly

Exposure of cells to a variety of external signals causes rapid changes in plasma membrane morphology. Plasma membrane dynamics, including membrane ruffle and microspike formation, fusion or fission of intracellular vesicles, and the spatial organization of transmembrane proteins, is directly controlled by the dynamic reorganization of the underlying actin cytoskeleton. Two members of the Rho family of small GTPases, Cdc42 and Rac, have been well established as mediators of extracellular signaling events that impact cortical actin organization. Actin-based signaling through Cdc42 and Rac ultimately results in activation of the actin-related protein (Arp) 2/3 complex, which promotes the formation of branched actin networks. In addition, the activity of both receptor and non-receptor protein tyrosine kinases along with numerous actin binding proteins works in concert with Arp2/3-mediated actin polymerization in regulating the formation of dynamic cortical actin-associated structures. In this review we discuss the structure and role of the cortical actin binding protein cortactin in Rho GTPase and tyrosine kinase signaling events, with the emphasis on the roles cortactin plays in tyrosine phosphorylation-based signal transduction, regulating cortical actin assembly, transmembrane receptor organization and membrane dynamics. We also consider how aberrant regulation of cortactin levels contributes to tumor cell invasion and metastasis.     

Deleted in liver cancer protein family in human malignancies (Review)

The Deleted in Liver Cancer (DLC) protein family comprises proteins that exert their function mainly by the Rho GTPase-activating protein (GAP) domain and by regulation of the small GTPases. Since Rho GTPases are key factors in cell proliferation, polarity, cytoskeletal remodeling and migration, the aberrant function of their regulators may lead to cell transformation. One subgroup of these proteins is the DLC family. It was found that the first identified gene from this family, DLC1, is often lost in hepatocellular carcinoma and may be involved as a tumor suppressor in the liver. Subsequent studies evaluated the hypothesis that the DLC1 gene acts as a tumor suppressor, not only in liver cancer, but also in other types of cancer. Following DLC1, two other members of the DLC protein family, DLC2 and DLC3, were identified. However, limited published data are available concerning the role of these proteins in malignant transformation. This review focuses on the structure and the role of DLC1 and its relatives in physiological conditions and summarizes data published thus far regarding DLC function in the neoplastic process.