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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 13  |  Issue : 1  |  Page : 2-8

ABCs of RhoGTPases indicating potential role as oncotargets


Department of Phytochemistry and Pharmacognosy, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad, Gujarat, India

Date of Web Publication16-May-2017

Correspondence Address:
Neeta Shrivastava
B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad - 380 054, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.204878

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 > Abstract 

RhoGTPases also known as molecular switches represent a family of GTP-binding proteins. They shuttle between “On” and “Off” states. In the “On” state, they activate plethora of molecules. These proteins perform a wide variety of functions involving cytoskeletal modeling, cell motility, migration, and mitosis. Members of this family are referred as master regulators of many cellular activities. Due to wide variety of portfolios attributed to RhoGTPases, their misbehavior leads to initiation and also progression of metastatic cancers. Many members of this family have been reported to be differentially regulated leading to spread of malignant cells from one site to other. These wandering cells find a comfortable site in accordance to Paget's soil and seed hypothesis and form secondary lesions. Out of multiple members of this family, RhoA and RhoC are important factors. RhoA is supposed to increase tumor proliferation when overexpressed while RhoC is responsible for tumor initiation. We searched publications on RhoGTPases, their functions and contribution in cancer development and metastasis on World Wide Web and PubMed. This review focuses on the role of Rac and Rho small GTPases in cell motility and granting the opportunistic motile behavior of aggressive cancer cells. To condense knowledge from existing literature about the roles played by these molecular switches, their structural and functional ramifications are introduced in the beginning followed by an account on their wrong behavior that leads to oncogenesis and oncoprogression. This piece of work highlights members of RhoGTPases as viable oncotargets.

Keywords: Cancer, epithelial-mesenchymal transition, invasion, metastasis, oncotargets, RhoGTPases


How to cite this article:
Bora I, Shrivastava N. ABCs of RhoGTPases indicating potential role as oncotargets. J Can Res Ther 2017;13:2-8

How to cite this URL:
Bora I, Shrivastava N. ABCs of RhoGTPases indicating potential role as oncotargets. J Can Res Ther [serial online] 2017 [cited 2017 Jun 27];13:2-8. Available from: http://www.cancerjournal.net/text.asp?2017/13/1/2/204878


 > Introduction Top


Intricate signaling pathways are key determinants in oncogenesis and metastasis. In a classical paper by Hanahan and Weinberg, probable hallmarks of carcinogenesis have been enumerated.[1],[2] To quote few of them, are uncontrolled growth, bypassing cell death, self-sustaining nutrient supply, escaping immune surveillance, voyages to distant sites, i.e., metastasis. In metastasis, cancer cells migrate from the primary site, a process called as intravasation into the bloodstream and localize to distant sites by a process called as extravasation.[3] In the bloodstream, these cells can be dormant and may form micrometastasis foci in the presence of (presently unknown) signals.[4] These foci inhabit a new site with favorable microenvironment in accordance to Paget's soil and seed hypothesis.[5],[6] These metastatic foci are more aggressive than primary lesions and hence understanding their basic biology will help in unraveling better therapeutic targets.

The process of metastasis is majorly dependent on inappropriate migratory phenotype which in turn relies on cytoskeleton. Actin and tubulin are major players of this process. They are highly versatile, dynamic polymers capable of organizing and maintaining intracellular compartmentalization, defining cell polarity, molecular trafficking and generating both pushing and contractile forces necessary for movement.[7] During cell migration, they generate protrusive forces at the front and retraction forces at the rear. These activities of actin and tubulin are guided and regulated by a plethora of signaling molecules. Rho, Rac, Cdc42 belonging to RhoGTPases family being the most important regulators.

RhoGTPases form a distinct family within the Ras-like protein superfamily, which also includes the Ras, Rab, Arf, and Ran families.[8] Rho proteins are highly conserved from lower eukaryotes to plants and mammals. In humans, the family comprises 21 members, divided into 6 different subfamilies.[9] RhoGTPases act as molecular switches between GTP-bound active and GDP-bound inactive forms.[10] Activated GTPases binds to multitude of effector molecules (<100). Cell type-specific expression of these effectors determines RhoGTPase function. This activity is regulated by

  1. Guanine nucleotide exchange factors (GEFs) that catalyze activation step by exchange of GDP to GTP. About 79 GEFs are known to be responsible for the activation of mammalian RhoGTPases [11]
  2. A group of 80 GTPase activating proteins (GAPs) mediate inactivation by stimulating intrinsic GTPase activity [12]
  3. Guanine nucleotide dissociation inhibitors (GDIs) who blocks spontaneous activation [13] by sequestering them into the cytoplasm in their inactive state.[14]


Since RhoGTPases regulates cytoskeletal proteins; hence, they play very important role in cell cycle progression, cytokinesis, epithelial cell morphogenesis, most importantly migration.[15] Since RhoGTPases play diverse functions, hence, their involvement in disease progression cannot be overlooked. This review focuses mainly on their role in cancer development and metastasis.


 > Rhogtpases and Their Role in Four M's Top


The biology of the RhoGTPases family of proteins is clearly too large and is beyond the scope of this review. Contributions have, therefore, been selected so as to focus on their role on three M's relevant to cancer and where the cytoskeleton plays a prominent part i.e., (i) Mitosis, (ii) Morphogenesis, (iii) Migration, and (iv) Metastasis. A pictorial presentation of functionally diverse proteins of this family is shown in [Figure 1]. RhoGTPases act as a node from where a variety of extracellular signals converge and bring a variety of functions.[16]
Figure 1: RhoGTPases serve as point of intersection of different signaling cascades. In response to various stimulating signals, such as growth factors, chemokines, matrix proteins, they mediate activation of diverse effector molecules. These effectors then bring their respective effects. Thus, making RhoGTPases as central molecules in diverse pathways

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 > Rhogtpases and Mitosis Top


Cell division is a tightly regulated process that occurs only in the presence of specific conditions such as growth factors and extra cellular contacts. Each step is highly controlled so that a cell passes all the phases systematically. Cancer cells are hyperproliferative cells that have lost control over these cell division checkpoints. A typical eukaryotic cell cycle consists of synthesis phase, and a karyokinesis phase that is M phase. Both the phases are temporally separated by G1 and G2 phase. Cyclin-dependent kinases (Cdks) are activated under the influence of RhoGTPases in G1 phase. Moreover, prolonged Rac activation induces cyclin D1 expression and thus promote cell proliferation.[17] Similarly, microtubule organization and actin cytoskeleton reorganization during M phase are dependent on RhoGTPases. Growth factors, nutrients, cell-cell or cell-matrix interactions guide the onset of G1 progression by activating cascades of intracellular pathways. RhoA, Cdc42, and Rac1 are ubiquitously expressed RhoGTPases that stimulate cell cycle. Rac1 and RhoA promote G1-S transition by increasing the amounts of cyclin D1, while RhoA was additionally shown to negatively regulate the levels of the cell cycle inhibitors p21cip1 and p27kip1.[18],[19] For cell cycle transition, high demands of cyclins are fulfilled by sustained activation of ERK pathway under the influence of signals from integrin-mediated cell adhesion.[20] RhoGTPases dictates the attachment of adhesion complexes with cytoskeleton. In addition, clustered integrins in a positive feedback loop activates RhoGTPases by recruiting additional GEFs. RhoD exerts a positive regulation of G1/S phase whereas RhoE decreases cell proliferation by decreasing cyclin D1. RhoA and ROCK plays important role in cell furrow formation during cytokinesis.[21]


 > Rhogtpases and Morphogenesis Top


Tissue architecture is fundamental to multicellular organisms. In mammals, epithelial cells are polarized with apical and basolateral membrane domains. These cells are interconnected by zonula occludens (tight junctions) and zonula adherens. Although these complexes have differences in protein architecture share functional similarities in forming extracellular adhesive contacts and intracellular collaborations with actin cytoskeleton, signaling pathways. Junctional complexes are initially formed by Rac1 and Cdc42, further interacting with Par6/aPKC complex promotes apical-basal polarity.[22] Different cell types such as keratinocytes develop loss of adherens junctions in the absence of Rho and Rac proteins. Adherens and tight junctions are supposed to be essential in maintaining intimate cell to cell contact. Activation of Rho and Rac was shown to increase the amount of cytoskeleton-associated e-cadherin and β-catenin, while blocking of these components led to the disappearance of cadherins from adherens junctions.[23] Loss of junctional complexes leads to loss of polarity and thus loss of epithelial phenotype. Hence, RhoGTPases are believed to be responsible for transition from epithelial to mesenchymal morphology.


 > Rhogtpases and Migration Top


Cell migration is a very important process not only in development but also during wound repair, immune surveillance. Attractants and repellents guide the cell movement. These can be locally or distantly acting soluble factors released by adjoining cells or extracellular matrix. Posttranslational modifications such as ubiquitination of small GTPases influences their localization, stability, and function with respect to cell migration and division.[24] Animal cells migrate by frontal actin polymerization, filament elongation in conjunction with actin-myosin filament contraction at the rear end. GTP-bound Rac accumulates at the front end and promotes actin polymerization to push the leading edge membrane of migrating cells. Rho generates contractile forces through ROCK-mediated myosin light chain phosphorylation which helps in cross-linking actin and thus moving the cyton forward.[25] New integrin complex formation is also forbidden under the influence of ROCK which becomes important for avoiding lateral protrusions. In culture, cells can migrate randomly due to series of positive and negative feedback loops involving Rho, Rac, etc., while they can attain directional sensing in vivo. Directional migration is usually due to the reorganization of microtubules and centrosomes. This facilitates long distance journeys. This polarized migration is regulated mainly by Cdc42. In its GTP-bound active state, it activates Par complex at the leading edge of migrating cell. This in turn schedules microtubule reorganization essential for migration.


 > Rhogtpases and Metastasis Top


Metastatic tumor cells display uncontrolled proliferation, loss of epithelial cell polarity, altered interactions with neighboring cells and the surrounding extracellular matrix, and enhanced migratory properties. Animals have 3 Rho isoforms, RhoA, RhoB, and RhoC, sharing 85% amino acid sequence identity. Despite their similarity, both modulators (GEFs and GAPs) and downstream effectors show favored interaction with single Rho isoforms, and the three proteins play differential roles in cells. Key steps in invasion and metastasis include alterations in cell adhesion, cell-matrix and cell-cell interactions, and the acquisition of an increased migratory phenotype. Line diagrams showing role of RhoA and C have been depicted in [Figure 2] and [Figure 3]. Proteins of the RhoGTPase family regulate all these processes in cell culture, and for that reason, RhoGTPases, their regulators, and their effectors have been suggested to control tumor formation and progression in humans. Cdc42 dicates filopodia formation while Rac activation leads to lamellipodia formation both of which are essential for migration. Activated Cdc42 enhances β1 integrin expression and thus fosters transendothelial migration leading to metastasis.[26]
Figure 2: Downstream effects of RhoA GTPase signaling

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Figure 3: RhoC signaling and its effector functions

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Germline mutations leading to loss of function in any of these regulators or effectors may result in weaker impairment of RhoGTPase activity. Mutations in RhoGTPases have been rarely observed except in RhoH, rather deregulation is indirect involving alterations in their expression or activation. The following section summarizes genetic alterations and their effect on RhoGTPases. The evidence for Rho family member involvement in human cancer has been recently reviewed. They are rarely been reported to be mutated while their expression is frequently altered.[27] For instance RhoA, RhoC, Rac1, Rac2, Rac 3, Cdc42 etc., are overexpressed, RhoB is often downregulated as in ovarian cancer by histone deacetylation.[28] RhoA is overexpressed in head and neck squamous carcinomas [29] as well as in lung, colon, and breast tumors.[30] In the case of breast tumors, increasing RhoA expression correlated with increasing tumor grade, suggesting a role for RhoA in tumor progression. RhoC overexpression is found in breast carcinoma,[31] squamous Cell Carcinomas of the head and neck [32] pancreatic adenocarcinoma, prostate cancer cell lines.[33] Breast cancer is also associated with overexpression of Rac1 and Cdc42. Rac1 is overexpressed in testicular, breast, gastric prostate, and lung cancers. Rac2 has been restricted to hematopoietic lineage without being directly related to oncogenesis. Rac3 activity has been found to be elevated in breast cancer.[34] [Table 1] highlights aberrant role of RhoGTPase family members in different cancer types.[9],[16],[35],[36] RhoA, RhoB, and RhoC can all induce stress fibers when overexpressed, and the Clostridium botulinum exoenzyme C3 transferase, which modifies all three isoforms, induces loss of stress fibers and inhibits cell migration.[37] However, several lines of evidence indicate that the isoforms have different functions. For example, RhoA and RhoC are geranylgeranylated and localize to the plasma membrane or interact with RhoGDI in the cytoplasm, whereas RhoB localizes to endosomal membranes because of its unique C-terminal lipid modifications (farnesylated or a geranylgeranylated and is also palmitoylated) and regulates endosomal trafficking of membrane receptors.[38],[39] Some RhoA is localized on the plasma membrane depending on the cell type. Active RhoA is found predominantly in membrane ruffles in the leading lamella and/or at the rear or back of migrating cells [40] consistent with a role in cell migration. RhoA also contributes to cytokinesis and is localized to the cleavage furrow. RhoA might play a role during tumor cell proliferation and survival.[41] For example, in vitro, constitutively active RhoA can stimulate transformation and affects epithelial disruption during tumor progression.[42] Recurrence, poor prognosis have been correlated with overexpression of RhoA. Recently, overexpression of wild-type RhoA was shown to increase metastasis formation of ovarian cancer cells injected into the peritoneal cavity, supporting the notion that overexpression of wild type RhoA is sufficient to promote tumor progression.
Table 1: The family of RhoGTPases (21 members)*


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Knockout mouse models indicate that RhoB has a potential tumor suppressor function since its loss lead to tumor progression and its expression was decreased in highly poorly differentiated invasive squamous cell carcinoma. Loss of RhoB does not promote hyperproliferation by itself rather in tumors due to chemical induction causes decreased apoptosis. Adenovirus-mediated ectopic expression of RhoB in ovarian xenografts in nude mice resulted in reduced tumor growth. It is activated in response to several stress stimuli including DNA damage or hypoxia, and it has been reported to inhibit tumor growth, cell migration, and invasion and have proapoptotic functions in cells. RhoC is required specifically for metastasis.[43],[44] In terms of cell motility, overexpression of RhoC-stimulated melanoma cell motility to a greater degree than RhoA overexpression. Overexpression of wild-type RhoC has also been shown to stimulate motility and in vitro invasion in breast carcinoma cells.[45] Furthermore, RhoA often inhibits whereas RhoC enhances cancer cell invasion in vitro.[46],[47] Squamous cell carcinoma, breast cancer, bladder cancer, and ovarian cancer have been reported to be poorly prognosed with high invasiveness due to enhanced expression of RhoC. In contrast to RhoA, RhoC has no apparent transforming activity and the involvement of RhoC in cancer progression appears to be restricted largely to metastasis.[44] RhoD has been shown to participate in fibroblast motility, and RhoE is involved in the motility of MDCK epithelial cells, the involvement of other Rho proteins in carcinoma cell motility warrants further investigation.[48] RhoE has been shown to downregulated in esophageal squamous cell carcinoma cell lines functioning as tumor suppressors through EGFR/ERK pathway.[49] RhoJ has been indicated to positively regulate tumor cell motility and invasiveness in gastric cancers.[50]

Cells from several origins, and among them cancer cells are particularly talented, can engage ad hoc epigenetic/ontogenetic programs enabling them to adapt to environmental changes. This ability of cells, commonly referred as cell plasticity, is often related to different strategies to move in three-dimensional tissues. Loss of epithelial-like cell morphology to adopt a motile phenotype has been termed epithelial-mesenchymal transition (EMT).[51] PI3K can induce the activation of Rho, Rac and Cdc42, which in turn lead to the generation of phosphatidylinositol (3, 4, 5)-trisphosphate promoting existence of a feedback loop between Rho proteins and PI3K. This signaling is important for epithelial–mesenchymal transition.[52]In vitro epithelial–mesenchymal transition was induced by expression of the Ras oncogene in MDCK cells because of shift in balance between Rac and Rho activity.[53] Adhesion to fibronectin leads to the activation of both Rac and Rho and as a consequence to increased cyclin D1 levels and to downregulation of the Cdk inhibitor p21WAF1. RhoC is selectively upregulated during EMT, which occurs in some cancers.[54] During EMT, the upregulation of alpha-smooth muscle actin can be blocked by inhibiting the expression of RhoA, but not by that of RhoB or RhoC. This effect is independent of Rho-kinase activity. RhoC is the isoform solely responsible for stress fiber formation and inhibiting its expression reduces EMT-induced migration by 50%.


 > Targeting Aberrant Rho Signaling as Anticancer Strategy Top


Rho proteins play important biological functions and are hence highly posttranslationally modified. They undergo a complex series of posttranslational modifications that are directed by the presence of a so-called CaaX motif at their C-terminus. This posttranslational pathway is termed as protein prenylation. This involves attachment of an isoprenoid lipid to an invariant cysteine residue of the CaaX motif. An enzymatically catalyzed reaction covalently attaches either a 15-carbon farnesyl or 20-carbon geranylgeranyl isoprenoid to this cysteine usually done by protein farnesyltransferase (FTase) or protein geranylgeranyltransferase-I (GGTase-I), respectively.[55] Most Rho family members are geranylgeranylated. Pharmacologic targeting of the enzymes involved in the CaaX-processing pathway has emerged as a promising anticancer strategy. In particular, there has been much effort in designing inhibitors against the protein prenyltransferases, most notably FTase. There is also recent evidence that the inhibition of geranylgeranylation of Rho proteins also impacts oncogenesis and metastasis. However, the overall success of the FTase inhibitors (FTIs) in the clinical setting has been somewhat disappointing. This may be attributed to alternate prenylation. Alternatively, geranylgeranyl pyrophosphate (GGPP) which is a precursor for prenylation by GGTase can be targeted. GGPP can be reduced dramatically by inhibiting mevalonate synthesis by inhibiting HMG-CoA reductase, a key enzyme in cholesterol biosynthetic pathway. Genome-wide short hairpin RNA studies have revealed 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 and geranylgeranyl diphosphate synthase 1 as top scoring targets in the mevalonate pathway.[56] Statins are a class of drugs that can reduce HMG-CoA.[57] The scope of drug discovery has also been limited since proteins with hydrophobic pockets only are considered druggable. Dual inhibitor, Y16, of enzyme-substrate interface such as RhoA-GEF have been shown to improve efficacy and specificity.[58] [Table 2] enlists few of these molecules currently under different levels of investigations. Although clinical trials of FTIs entered many years back yet there is still long way to hit the market owing to multiple targets of these transferases, toxicity with other transferase inhibitors.
Table 2: RhoGTPase targeted therapies


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Initial studies indicated RhoGTPases as regulators of cytoskeleton dynamics. Recent studies have updated their role in modulating transcription, cell division, survival, intracellular molecule trafficking, intercellular, and cell-matrix interactions. This review highlighted how RhoGTPases work in the cells and how they influence tumor growth and metastasis. The description looks very simple, but within the cell, it is intricately woven with other signaling pathways. Simultaneous effect of RhoGTPases on cyclin D1 and p21/27 are important for G1-S progression. Since both the key positive as well as negative regulators of G1 progression are under the control of RhoGTPases; hence, they have high potential to deregulate cell cycle progression. Moreover, these are central players in maintaining cellular architecture and providing cell shape. Loss of morphology increases their tendency to survive independently as a result of acquiring mesenchymal phenotype. This highly motile stage along with capability to migrate increases invasiveness of certainly all types of cancers, thus imparting RhoGTPases to serve as attractive therapeutic targets.

Financial support and sponsorship

Indian Council of Medical Research, India, supported the study by providing financial assistance in terms of scholarship to Ms. Indira (ICMR-JRF-2008/MPD-6 (31291)), Nirma University Ahmedabad, for accepting her as a PhD scholar.[62]

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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