RAC1 Takes the Lead in Solid Tumors

De, Pradip; Aske, Jennifer C.; Dey, Nandini

doi:10.3390/cells8050382

Cited by 81 publications

(77 citation statements)

References 103 publications

(115 reference statements)

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“…In cancer, Rac1 and Cdc42 are mutated, overexpressed and (or) hyperactivated. Hyperactivation of Rac and Cdc42 is primarily due to signaling via oncogenic upstream receptors, which in turn stimulate GEF activity (Arias-Romero and Chernoff, 2013; Kazanietz and Caloca, 2017;Maldonado and Dharmawardhane, 2018;De et al, 2019). However, GEFs themselves can become oncogenic by mutation or dysregulated expression ( Table 1).…”

Section: Type Of Cancermentioning

confidence: 99%

“…These receptors include RTKs, GPCRs, and integrins, which signal to other oncogenes such as PI3-K and Ras that can in turn activate Rac/Cdc42 GEFs, which themselves can be oncogenic (Figure 1). Therefore, upregulated Rac and Cdc42 can drive malignant signaling during acquisition of resistance to cancer therapies targeting cell surface receptors, by acting downstream of therapy resistance mechanisms such as Ras/MAPK and PI3-K/mTOR signaling (Baker et al, 2014;Cardama et al, 2018;Maldonado and Dharmawardhane, 2018;De et al, 2019).…”

Section: Rac/cdc42 Inhibitors In Therapy Resistancementioning

confidence: 99%

“…The pivotal role of Rac and Cdc42 in multiple cancers has been extensively reviewed by us and others (Pai et al, 2010;Mack et al, 2011;Stengel and Zheng, 2011;Wertheimer et al, 2012;Bid et al, 2013;Kazanietz and Caloca, 2017;Casado-Medrano et al, 2018;Maldonado and Dharmawardhane, 2018;De et al, 2019). In addition, the related Rho GTPase Rho has also been implicated in tumorigenesis and cancer progression.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.

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Section: Type Of Cancermentioning

confidence: 99%

Section: Rac/cdc42 Inhibitors In Therapy Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Maldonado

Medina

Velázquez

et al. 2020

Front. Cell Dev. Biol.

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“…Rac1 is a multifunctional protein and regulate several cellular responses by regulating downstream effectors beside its role in scaffolding protein. It is found that Rac1 plays a crucial role in progression of cancers [25]. QPCR analysis indicates that Rac1 significantly downregulate after silibinin treatment.…”

Section: Discussionmentioning

confidence: 99%

Silibinin Inhibit Cell Migration through Downregulation of RAC1 Gene Expression in Highly Metastatic Breast Cancer Cell Line

et al. 2020

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Background Triple negative breast cancer is the most invasive breast cancer subtype and possesses poor prognosis and survival. Rho GTPase famil, especially Rac1 participates in a number of signaling events in cells with crucial roles in malignancy, migration and invasion of tumor cells. Silibinin, a flavonoid antioxidant from milk thistle has attracted attention in the recent decades for chemoprevention and chemotherapy of tumor cells. In this study, the effect of silibinin on the migration capacity of MDA-MB-231 cells, a highly metastatic human breast cancer cell line was investigated by evaluation of Rac1 expression. Method MTT wound healing and transwell assays were performed to evaluate the effects of silibinin on proliferation and migration of MDA-MB-231 cells. In addition, the influence of the silibinin on the expression of Rac1mRNAs was assessed by RT-PCR. Results Results indicated significant dose-dependent inhibitory effect of silibinin on proliferation and migration of MDA-MB-231 cells. It significantly inhibited the expression of Rac1 mRNA. Conclusion In conclusion, the results demonstrate that the silibinin can be used as an experimental therapeutic for the management of TNBC metastatic cancer.

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“…Compared with the Naive group, the alveolar septum of the IR group at each time points was signi cantly thickened and the alveolar in ltrated with in ammatory cells ( Figure 1A-B), the proportion of collagen bers increased signi cantly from the 1 st week to the 12 th week ( Figure 1C-D), indicating that pulmonary in ammation and brosis was induced by IR. Intraperitoneal injection of NSC23766, an inhibitor of Rac1 14 , could signi cantly alleviate RILI both in the Low dose (4mg/kg) and the High dose (8mg/kg) groups, manifested as reduction in the thickening of the alveolar septum ( Figure 1A-B) and decrease in collagen ber proportion ( Figure 1C-D). Besides, the IR-induced up-regulation of Vimentin, γ-H 2 AX and TGF-β, which were important indicators of epithelial-mesenchymal transition (EMT) 15 , DNA damage and IR-induced injury, were also inhibited by NSC23766 treatment ( Figure 1E-F, Supplemental material, S1A-D).…”

Section: Rili Was Alleviated By Rac1 Inhibitionmentioning

confidence: 99%

Inhibition of Rac1 Attenuates Radiation-Induced Lung Injury while Sensitizes Lung Tumor to Radiotherapy

Yan

et al. 2020

Preprint

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Backgrounds: There is still little progress in the effective treatment of radiation-induced lung injury (RILI), a key dose-limiting factor for thoracic radiotherapy. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatase involved in various mechanisms of radiation-induced damage and is over-expressed/mutated in various tumors. The gain-of-function mutation of Rac1 mediates tumor cells’ resistance to radiotherapy. Therefore, inhibiting Rac1 has the potential of protecting normal tissues from radiation-induced injury, and at the same time, sensitizing tumor to radiation therapy, which makes it a promising ideal target for radiation protection. To investigate the protective effects and mechanisms of Rac1 inhibition on RILI, and explore the possible mechanisms that mediate the differential effects of Rac1 inhibition on normal lung tissue and tumor cells.Methods: 60Co radioactive source was used for ionizing radiation (IR). RILI mouse model was constructed. Influence of Rac1 inhibition which was achieved by Rac1-specific inhibitor, NSC23766, on RILI were studied by H & E and Masson staining, and immunohistochemical staining of vimentin, TGF-βand γ-H2AX. Normal mouse lung epithelial cell line, MLE-12, and mouse lung cancer cell line, LLC, were used to study the effects of Rac1 inhibition on the cellular level. RNA-seq analysis was used for screening differential gene expression caused by Rac1 knockdown. The molecular mechanisms of Rac1 inhibition were studied at the cellular level. Subcutaneous tumor-bearing nude mouse model and orthotopic lung tumor-bearing mouse model were constructed to verify the bidirectional effects of Rac1 inhibition in vivo. Results: RILI of mouse was alleviated by intraperitoneal injection of NSC23766. Rac1 inhibition/knockdown reduced the radiation-induced damage of MLE-12 while aggravated that of LLC. Rac1 translocated from cytoplasm to nucleus after radiation. Tumor protein p53-inducible nuclear protein 1, Trp53inp1, was down-regulated by Rac1 knockdown. In vivo study further proved the differential effects of Rac1 inhibition. Rac1 was over-expressed and mutated in LLC cells, and the expression level of Trp53inp1 significantly lower, compared with that of MLE-12.Conclusion: Rac1 inhibition reduced the radiation-induced damage of normal lung epithelial cells, thereby alleviating RILI of mouse. These effects were partially mediated by down-regulating the expression of Trp53inp1. However, Rac1 inhibition significantly increased the sensitivity of LLC to radiation damage and inhibited its growth. The over-expression and mutation of Rac1, and the significant low expression of Trp53inp1 in LLC, may be the fundamental reasons mediating the differential effects of Rac1 inhibition.

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RAC1 Takes the Lead in Solid Tumors

Cited by 81 publications

References 103 publications

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

Silibinin Inhibit Cell Migration through Downregulation of RAC1 Gene Expression in Highly Metastatic Breast Cancer Cell Line

Inhibition of Rac1 Attenuates Radiation-Induced Lung Injury while Sensitizes Lung Tumor to Radiotherapy

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