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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 53933

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Special Issue Editor

Prof. Dr. Suranganie F. Dharmawardhane

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Guest Editor

Department of Biochemistry, School of Medicine, University of Puerto Rico-Medical Sciences Campus San Juan, Puerto Rico, USA
Interests: Rho GTPases; Rac; Cdc42; Experimental therapeutics targeting Rac/Cdc42; breast cancer; metastasis; signaling in cancer; cancer therapy resistance mechanisms

Special Issue Information

Dear Colleagues,

Rho GTPases have emerged as pivotal drivers of cancer metastasis in multiple cancer types. Therefore, understanding their dysregulation in cancer, and developing drugs to inhibit the activation of Rho GTPases has become a priority. Rho GTPases regulate cancer cell motility and invasion, which are a hallmark of metastasis. Even though oncogenic point mutations and splice variants have been reported from a number of cancers, Rho GTPases do not have to be mutated in cancer to drive cancer progression.

Rho GTPases are activated via the dysregulation of expression and/or activity of a myriad of oncogenic cell surface receptors: integrins, G protein coupled receptors, growth factor receptors, cytokine receptors, wnt, and notch signaling, etc., which converge on Rho GTPases by conveying signals through guanine nucleotide exchange factors. In turn Rho GTPases signal to multiple downstream effectors that regulate migration/invasion via de novo actin polymerization, cell polarization, metastasis, epithelial to mesenchymal transition (EMT), transcription, cell proliferation, cell cycle progression, apoptosis/survival, vesicle trafficking, angiogenesis, immune function, cell-cell and cell-substrate adhesions, and therapy resistance.

Much effort has been directed towards drugging the Rho GTPases; however, these drugs have yet to reach clinical trials. This special issue will highlight the current understanding of Rho GTPases in cancer with an emphasis on recognizing their central importance as critical targets for metastatic cancer therapy, for modulation of immunotherapies, and for chemosensitization of current therapeutic strategies.

Prof. Dr. Suranganie F. Dharmawardhane
Guest Editor

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Keywords

Rac
Rho
Cdc42 mechanism of action in cancer
dysregulation in metastatic cancer
immune modulation
Rho GTPases as therapeutic targets

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

2 pages, 175 KiB

Open AccessEditorial

Rho Family GTPases in Cancer

by Suranganie Dharmawardhane

Cancers 2021, 13(6), 1271; https://doi.org/10.3390/cancers13061271 - 12 Mar 2021

Cited by 4 | Viewed by 1512

Abstract

This Special Issue containing seminal contributions from international experts highlights the current understanding of Rho GTPases in cancer, with an emphasis on recognizing their central importance as critical targets for cancer therapy and for chemosensitization of current therapeutic strategies [...] Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

Research

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14 pages, 7786 KiB

Open AccessArticle

Drug Vulnerabilities and Disease Prognosis Linked to the Stem Cell-Like Gene Expression Program Triggered by the RHO GTPase Activator VAV2 in Hyperplastic Keratinocytes and Head and Neck Cancer

by Luis Francisco Lorenzo-Martín, Mauricio Menacho-Márquez and Xosé R. Bustelo

Cancers 2020, 12(9), 2498; https://doi.org/10.3390/cancers12092498 - 3 Sep 2020

Cited by 6 | Viewed by 2961

Abstract

We have recently shown that VAV2, a guanosine nucleotide exchange factor that catalyzes the stimulation step of RHO GTPases, is involved in a stem cell-like (SCL) regenerative proliferation program that is important for the development and subsequent maintenance of the tumorigenesis of both cutaneous (cSCC) and head and neck squamous cell carcinomas (hnSCC). In line with this, we have observed that the levels of the VAV2 mRNA and VAV2-regulated gene signatures are associated with poor prognosis in the case of human papillomavirus-negative hnSCC patients. These results suggest that the SCL program elicited by VAV2 in those cells can harbor therapeutically actionable downstream targets. We have addressed this issue using a combination of both in silico and wet-lab approaches. Here, we show that the VAV2-regulated SCL program does harbor a number of cell cycle- and signaling-related kinases that are essential for the viability of undifferentiated keratinocytes and hnSCC patient-derived cells endowed with high levels of VAV2 activity. Our results also show that the VAV2-regulated SCL gene signature is associated with poor hnSCC patient prognosis. Collectively, these data underscore the critical role of this VAV2-regulated SCL program for the viability of both preneoplastic and fully transformed keratinocytes. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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19 pages, 3831 KiB

Open AccessArticle

RAC1B Induces SMAD7 via USP26 to Suppress TGFβ1-Dependent Cell Migration in Mesenchymal-Subtype Carcinoma Cells

by Hendrik Ungefroren, Anuradha Kumarasinghe, Melina Musfeldt, Christian Fiedler, Hendrik Lehnert and Jens-Uwe Marquardt

Cancers 2020, 12(6), 1545; https://doi.org/10.3390/cancers12061545 - 11 Jun 2020

Cited by 7 | Viewed by 3053

Abstract

The small GTPase RAC1B has been shown to act as a powerful inhibitor of the transforming growth factor (TGF)β type I receptor ALK5 and TGFβ1/ALK5-induced epithelial–mesenchymal transition and cell motility. However, the precise mechanism has remained elusive. RNAi-mediated knockdown of RAC1B in the pancreatic ductal adenocarcinoma (PDAC)-derived cell line Panc1 failed to alter transcriptional activity from a transfected ALK5 promoter–reporter construct. In contrast, pharmacological inhibition of the proteasome decreased the abundance of ALK5 protein in cell lines of the mesenchymal subtype (Panc1, IMIM-PC-1, and breast cancer MDA-MB-231), but not in a PDAC cell line of the epithelial subtype (Colo357). Here, we focused on the inhibitory Smad protein, SMAD7, as a potential candidate for RAC1B-mediated inhibition of cell migration. In Panc1 cells devoid of RAC1B, SMAD7 protein was dramatically reduced and these cells were refractory to TGFβ1-induced upregulation of SMAD7 protein but not mRNA expression. Intriguingly, RNAi-mediated knockdown or ectopic overexpression of SMAD7 in Panc1 cells up- or downregulated, respectively, ALK5 protein expression and mimicked the suppressive effect of RAC1B on TGFβ/SMAD3-dependent transcriptional activity, target gene expression and cell migration. Transfection of SMAD7 was further able to partially rescue cells from the RAC1B knockdown-mediated increase in migratory properties. Conversely, knockdown of SMAD7 was able to partially rescue Panc1 and MDA-MB-231 cells from the antimigratory effect of ectopically expressed RAC1B. Finally, we demonstrate that RAC1B upregulation of SMAD7 protein requires intermittent transcriptional induction of the deubiquitinating enzyme USP26. Our data suggest that RAC1B induces SMAD7 by promoting its deubiquitination and establishes this Smad as one of RAC1B’s downstream effectors in negative regulation of ALK5 and TGFβ1-induced cell migration in mesenchymal-type carcinoma cells. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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17 pages, 3647 KiB

Open AccessArticle

P-REX1-Independent, Calcium-Dependent RAC1 Hyperactivation in Prostate Cancer

by Martin J. Baker, Martín C. Abba, Rafael Garcia-Mata and Marcelo G. Kazanietz

Cancers 2020, 12(2), 480; https://doi.org/10.3390/cancers12020480 - 19 Feb 2020

Cited by 10 | Viewed by 3862

Abstract

The GTPase Rac1 is a well-established master regulator of cell motility and invasiveness contributing to cancer metastasis. Dysregulation of the Rac1 signaling pathway, resulting in elevated motile and invasive potential, has been reported in multiple cancers. However, there are limited studies on the regulation of Rac1 in prostate cancer. Here, we demonstrate that aggressive androgen-independent prostate cancer cells display marked hyperactivation of Rac1. This hyperactivation is independent of P-Rex1 activity or its direct activators, the PI3K product PIP₃ and Gβγ subunits. Furthermore, we demonstrate that the motility and invasiveness of PC3 prostate cancer cells is independent of P-Rex1, supporting the analysis of publicly available datasets indicating no correlation between high P-Rex1 expression and cancer progression in patients. Rac1 hyperactivation was not related to the presence of activating Rac1 mutations and was insensitive to overexpression of a Rac-GAP or the silencing of specific Rac-GEFs expressed in prostate cancer cells. Interestingly, active Rac1 levels in these cells were markedly reduced by elevations in intracellular calcium or by serum stimulation, suggesting the presence of an alternative means of Rac1 regulation in prostate cancer that does not involve previously established paradigms. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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20 pages, 2542 KiB

Open AccessFeature PaperArticle

Inhibition of Rho-Associated Kinase Suppresses Medulloblastoma Growth

by Cecilia Dyberg, Teodora Andonova, Thale Kristin Olsen, Bertha Brodin, Marcel Kool, Per Kogner, John Inge Johnsen and Malin Wickström

Cancers 2020, 12(1), 73; https://doi.org/10.3390/cancers12010073 - 26 Dec 2019

Cited by 9 | Viewed by 4219

Abstract

Medulloblastoma is one of the most common malignant brain tumor types in children, with an overall survival of 70%. Mortality is associated with metastatic relapsed tumors. Rho-associated kinases (ROCKs), important for epithelial-mesenchymal transition (EMT) and proper nervous system development, have previously been identified as a promising drug target to inhibit cancer growth and metastatic spread. Here, we show that ROCKs are expressed in medulloblastoma, with higher ROCK2 mRNA expression in metastatic compared to non-metastatic tumors. By evaluating three ROCK inhibitors in a panel of medulloblastoma cell lines we demonstrated that medulloblastoma cells were sensitive for pharmacological ROCK inhibition. The specific ROCK inhibitor RKI-1447 inhibited the tumorigenicity in medulloblastoma cells as well as impeded cell migration and invasion. Differential gene expression analysis suggested that ROCK inhibition was associated with the downregulation of signaling pathways important in proliferation and metastasis e.g., TNFα via NFκβ, TGFβ, and EMT. Expression of key proteins in these pathways such as RHOA, RHOB, JUN, and vimentin was downregulated in ROCK inhibited cells. Finally, we showed that ROCK inhibition by RKI-1447 suppressed medulloblastoma growth and proliferation in vivo. Collectively, our results suggest that ROCK inhibition presents a potential new therapeutic option in medulloblastoma, especially for children with metastatic disease. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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12 pages, 1921 KiB

Open AccessArticle

RAC1B Suppresses TGF-β-Dependent Chemokinesis and Growth Inhibition through an Autoregulatory Feed-Forward Loop Involving PAR2 and ALK5

by Hannah Otterbein, Koichiro Mihara, Morley D. Hollenberg, Hendrik Lehnert, David Witte and Hendrik Ungefroren

Cancers 2019, 11(8), 1211; https://doi.org/10.3390/cancers11081211 - 20 Aug 2019

Cited by 7 | Viewed by 3656

Abstract

The small GTPase RAC1B functions as a powerful inhibitor of transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition, cell motility, and growth arrest in pancreatic epithelial cells. Previous work has shown that RAC1B downregulates the TGF-β type I receptor ALK5, but the molecular details of this process have remained unclear. Here, we hypothesized that RAC1B-mediated suppression of activin receptor-like kinase 5 (ALK5) involves proteinase-activated receptor 2 (PAR2), a G protein-coupled receptor encoded by F2RL1 that is crucial for sustaining ALK5 expression. We found in pancreatic carcinoma Panc1 cells that PAR2 is upregulated by TGF-β1 in an ALK5-dependent manner and that siRNA-mediated knockdown of RAC1B increased both basal and TGF-β1-induced expression of PAR2. Further, the simultaneous knockdown of PAR2 and RAC1B rescued Panc1 cells from a RAC1B knockdown-induced increase in ALK5 abundance and the ALK5-mediated increase in TGF-β1-induced migratory activity. Conversely, Panc1 cells with stable ectopic expression of RAC1B displayed reduced ALK5 expression, an impaired upregulation of PAR2, and a reduced migratory responsiveness to TGF-β1 stimulation. However, these effects could be reversed by ectopic overexpression of PAR2. Moreover, the knockdown of PAR2 alone in Panc1 cells and HaCaT keratinocytes phenocopied RAC1B’s ability to suppress ALK5 abundance and TGF-β1-induced chemokinesis and growth inhibition. Lastly, we found that the RAC1B knockdown-induced increase in TGF-β1-induced PAR2 mRNA expression was sensitive to pharmacological inhibition of MEK-ERK signaling. Our data show that in pancreatic and skin epithelial cells, downregulation of ALK5 activity by RAC1B is secondary to suppression of F2RL1/PAR2 expression. Since F2RL1 itself is a TGF-β target gene and its upregulation by TGF-β1 is mediated by ALK5 and MEK-ERK signaling, we suggest the existence of a feed-forward signaling loop involving ALK5 and PAR2 that is efficiently suppressed by RAC1B to restrict TGF-β-driven cell motility and growth inhibition. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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Review

Jump to: Editorial, Research

16 pages, 597 KiB

Open AccessReview

Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

by Laura Streit, Laurent Brunaud, Nicolas Vitale, Stéphane Ory and Stéphane Gasman

Cancers 2020, 12(7), 1859; https://doi.org/10.3390/cancers12071859 - 10 Jul 2020

Cited by 6 | Viewed by 3461

Abstract

Neuroendocrine tumors (NETs) belong to a heterogeneous group of neoplasms arising from hormone secreting cells. These tumors are often associated with a dysfunction of their secretory activity. Neuroendocrine secretion occurs through calcium-regulated exocytosis, a process that is tightly controlled by Rho GTPases family members. In this review, we compiled the numerous mutations and modification of expression levels of Rho GTPases or their regulators (Rho guanine nucleotide-exchange factors and Rho GTPase-activating proteins) that have been identified in NETs. We discussed how they might regulate neuroendocrine secretion. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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16 pages, 1449 KiB

Open AccessReview

Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors

by Pradip De, Brett James Rozeboom, Jennifer Carlson Aske and Nandini Dey

Cancers 2020, 12(6), 1541; https://doi.org/10.3390/cancers12061541 - 11 Jun 2020

Cited by 22 | Viewed by 4407

Abstract

Acting as molecular switches, all three members of the Guanosine triphosphate (GTP)-ase-family, Ras-related C3 botulinum toxin substrate (RAC), Rho, and Cdc42 contribute to various processes of oncogenic transformations in several solid tumors. We have reviewed the distribution of patterns regarding the frequency of Ras-related C3 botulinum toxin substrate 1 (RAC1)-alteration(s) and their modes of actions in various cancers. The RAC1 hyperactivation/copy-number gain is one of the frequently observed features in various solid tumors. We argued that RAC1 plays a critical role in the progression of tumors and the development of resistance to various therapeutic modalities applied in the clinic. With this perspective, here we interrogated multiple functions of RAC1 in solid tumors pertaining to the progression of tumors and the development of resistance with a special emphasis on different tumor cell phenotypes, including the inhibition of apoptosis and increase in the proliferation, epithelial-to-mesenchymal transition (EMT), stemness, pro-angiogenic, and metastatic phenotypes. Our review focuses on the role of RAC1 in adult solid-tumors and summarizes the contextual mechanisms of RAC1 involvement in the development of resistance to cancer therapies. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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37 pages, 4616 KiB

Open AccessReview

Rho GTPases in Gynecologic Cancers: In-Depth Analysis toward the Paradigm Change from Reactive to Predictive, Preventive, and Personalized Medical Approach Benefiting the Patient and Healthcare

by Pavol Zubor, Zuzana Dankova, Zuzana Kolkova, Veronika Holubekova, Dusan Brany, Sandra Mersakova, Marek Samec, Alena Liskova, Lenka Koklesova, Peter Kubatka, Jan Bujnak, Karol Kajo, Milos Mlyncek, Frank A. Giordano and Olga Golubnitschaja

Cancers 2020, 12(5), 1292; https://doi.org/10.3390/cancers12051292 - 20 May 2020

Cited by 14 | Viewed by 6063

Abstract

Rho guanosine triphospatases (GTPases) resemble a conserved family of GTP-binding proteins regulating actin cytoskeleton dynamics and several signaling pathways central for the cell. Rho GTPases create a so-called Ras-superfamily of GTPases subdivided into subgroups comprising at least 20 members. Rho GTPases play a key regulatory role in gene expression, cell cycle control and proliferation, epithelial cell polarity, cell migration, survival, and apoptosis, among others. They also have tissue-related functions including angiogenesis being involved in inflammatory and wound healing processes. Contextually, any abnormality in the Rho GTPase function may result in severe consequences at molecular, cellular, and tissue levels. Rho GTPases also play a key role in tumorigenesis and metastatic disease. Corresponding mechanisms include a number of targets such as kinases and scaffold/adaptor-like proteins initiating GTPases-related signaling cascades. The accumulated evidence demonstrates the oncogenic relevance of Rho GTPases for several solid malignancies including breast, liver, bladder, melanoma, testicular, lung, central nervous system (CNS), head and neck, cervical, and ovarian cancers. Furthermore, Rho GTPases play a crucial role in the development of radio- and chemoresistance e.g. under cisplatin-based cancer treatment. This article provides an in-depth overview on the role of Rho GTPases in gynecological cancers, highlights relevant signaling pathways and pathomechanisms, and sheds light on their involvement in tumor progression, metastatic spread, and radio/chemo resistance. In addition, insights into a spectrum of novel biomarkers and innovative approaches based on the paradigm shift from reactive to predictive, preventive, and personalized medicine are provided. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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17 pages, 1917 KiB

Open AccessReview

Dysregulation of Rho GTPases in Human Cancers

by Haiyoung Jung, Suk Ran Yoon, Jeewon Lim, Hee Jun Cho and Hee Gu Lee

Cancers 2020, 12(5), 1179; https://doi.org/10.3390/cancers12051179 - 7 May 2020

Cited by 48 | Viewed by 5618

Abstract

Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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49 pages, 2352 KiB

Open AccessReview

MicroRNA Regulation of the Small Rho GTPase Regulators—Complexities and Opportunities in Targeting Cancer Metastasis

by Brock A. Humphries, Zhishan Wang and Chengfeng Yang

Cancers 2020, 12(5), 1092; https://doi.org/10.3390/cancers12051092 - 28 Apr 2020

Cited by 14 | Viewed by 5304

Abstract

The small Rho GTPases regulate important cellular processes that affect cancer metastasis, such as cell survival and proliferation, actin dynamics, adhesion, migration, invasion and transcriptional activation. The Rho GTPases function as molecular switches cycling between an active GTP-bound and inactive guanosine diphosphate (GDP)-bound conformation. It is known that Rho GTPase activities are mainly regulated by guanine nucleotide exchange factors (RhoGEFs), GTPase-activating proteins (RhoGAPs), GDP dissociation inhibitors (RhoGDIs) and guanine nucleotide exchange modifiers (GEMs). These Rho GTPase regulators are often dysregulated in cancer; however, the underlying mechanisms are not well understood. MicroRNAs (miRNAs), a large family of small non-coding RNAs that negatively regulate protein-coding gene expression, have been shown to play important roles in cancer metastasis. Recent studies showed that miRNAs are capable of directly targeting RhoGAPs, RhoGEFs, and RhoGDIs, and regulate the activities of Rho GTPases. This not only provides new evidence for the critical role of miRNA dysregulation in cancer metastasis, it also reveals novel mechanisms for Rho GTPase regulation. This review summarizes recent exciting findings showing that miRNAs play important roles in regulating Rho GTPase regulators (RhoGEFs, RhoGAPs, RhoGDIs), thus affecting Rho GTPase activities and cancer metastasis. The potential opportunities and challenges for targeting miRNAs and Rho GTPase regulators in treating cancer metastasis are also discussed. A comprehensive list of the currently validated miRNA-targeting of small Rho GTPase regulators is presented as a reference resource. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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43 pages, 4015 KiB

Open AccessReview

Rac1 Signaling: From Intestinal Homeostasis to Colorectal Cancer Metastasis

by Larissa Kotelevets and Eric Chastre

Cancers 2020, 12(3), 665; https://doi.org/10.3390/cancers12030665 - 12 Mar 2020

Cited by 60 | Viewed by 8821

Abstract

The small GTPase Rac1 has been implicated in a variety of dynamic cell biological processes, including cell proliferation, cell survival, cell-cell contacts, epithelial mesenchymal transition (EMT), cell motility, and invasiveness. These processes are orchestrated through the fine tuning of Rac1 activity by upstream cell surface receptors and effectors that regulate the cycling Rac1-GDP (off state)/Rac1-GTP (on state), but also through the tuning of Rac1 accumulation, activity, and subcellular localization by post translational modifications or recruitment into molecular scaffolds. Another level of regulation involves Rac1 transcripts stability and splicing. Downstream, Rac1 initiates a series of signaling networks, including regulatory complex of actin cytoskeleton remodeling, activation of protein kinases (PAKs, MAPKs) and transcription factors (NFkB, Wnt/β-catenin/TCF, STAT3, Snail), production of reactive oxygen species (NADPH oxidase holoenzymes, mitochondrial ROS). Thus, this GTPase, its regulators, and effector systems might be involved at different steps of the neoplastic progression from dysplasia to the metastatic cascade. After briefly placing Rac1 and its effector systems in the more general context of intestinal homeostasis and in wound healing after intestinal injury, the present review mainly focuses on the several levels of Rac1 signaling pathway dysregulation in colorectal carcinogenesis, their biological significance, and their clinical impact. Full article

(This article belongs to the Special Issue Rho Family of GTPases in Cancer)

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