Rho GTPases as therapeutic targets in cancer (Review)

Cardama, Georgina Alexandra; González, Nazareno; Maggio, Julián; Menna, Pablo Lorenzano; Gomez, Daniel E.

doi:10.3892/ijo.2017.4093

Cited by 77 publications

(71 citation statements)

References 121 publications

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“…Together with our studies, the potential contribution of Rac1 to the resistance to anti-cancer chemotherapeutic drugs, highlights the critical need to develop treatment strategies to target Rac1 related pathways in a clinical setting 12 . Several chemical compound were developed for targeting Rac1 and showed anti-cancer effects in cell lines or animal models 60,61 . However, the GTPases are still hard to be targeted clinically in spite of numerous efforts to develop their inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

Qin

et al. 2020

Nat Commun

111

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Resistance development to one chemotherapeutic reagent leads frequently to acquired tolerance to other compounds, limiting the therapeutic options for cancer treatment. Herein, we find that overexpression of Rac1 is associated with multi-drug resistance to the neoadjuvant chemotherapy (NAC). Mechanistically, Rac1 activates aldolase A and ERK signaling which up-regulates glycolysis and especially the non-oxidative pentose phosphate pathway (PPP). This leads to increased nucleotides metabolism which protects breast cancer cells from chemotherapeutic-induced DNA damage. To translate this finding, we develop endosomal pH-responsive nanoparticles (NPs) which deliver Rac1-targeting siRNA together with cisplatin and effectively reverses NAC-chemoresistance in PDXs from NAC-resistant breast cancer patients. Altogether, our findings demonstrate that targeting Rac1 is a potential strategy to overcome acquired chemoresistance in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

Qin

et al. 2020

Nat Commun

111

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“…The Rho family of GTPases, e.g., Rac1 and the associated kinases, e.g., ROCK, are involved in key oncogenic signaling pathways, particularly by activating the actomyosin network and promoting cancer invasion and metastasis [26,27]. Up-regulation of Rac1 activity has been frequently observed in human cancer [28] and Rac1 inhibitor, such as NSC23766 that we used in this study, is being actively pursued as anticancer therapeutic.…”

Section: Discussionmentioning

confidence: 96%

Rac1/ROCK-driven membrane dynamics promote Natural Killer cell cytotoxicity via necroptosis

Zhu

Xie

Shi

2019

Preprint

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Natural Killer (NK) cells play a key role in eliminating virus-infected cells and cancer cells.Although molecular machineries mediating their activity and specificity have been extensively studied, our understanding of the determinants that govern the differential cytotoxicity of NK cells against distinct epithelial cell targets is still limited. By employing a live-cell FRET reporter and quantitative single cell imaging, we characterized the dynamic phenotypes and rate-limiting kinetics of a panel of normal and epithelial cancer cells to killing by primary human NK cells. We uncovered intriguing target-dependent variability in their sensitivity to three distinct NK cell cytotoxic modes mediated by granzyme, death ligand and the largely unexplored necrosis. While NK-target cell interaction via known inhibitory and activating receptors, in particular the KIRs, largely determined the overall cytotoxic activity, we found the variable sensitivity to distinct NK cell cytotoxic modes was not regulated by individual receptors. Instead, plasma membrane dynamics driven by blebs and/or lamellipodia appeared to control the induction of different cytotoxic modes in a target-specific manner, particularly promoting necrotic killing. Our results point to modulating the membrane dynamics of epithelial cell targets as a viable strategy to control the degree, timing and inflammatory consequences of NK cell killing.

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“…These results were also found in cRc (19) when Lgr5 was silenced, which shares ~50% sequence homology with Lgr6. Rho GTPases are regulated by Lgr5 (35) and have been shown to be involved in cell cycle entry and progression (36). As targeting Rho GTPases provides a therapeutic opportunity for patients with cancer (36), further investigations are required to identify whether Rho GTPases are regulated by Lgr6 in CRC.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Lgr6 inhibits proliferation and invasion and increases apoptosis in human colorectal cancer

Wang

Dai²,

Zhang³

et al. 2018

Int J Mol Med

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The aim of the present study was to analyze the role of leucine‑rich repeat‑containing G‑protein coupled receptor 6 (Lgr6) in the proliferation and invasion of colorectal cancer (CRC) cells, and to investigate its possible mechanisms. The expression of Lgr6 in CRC tissues was observed by real time‑quantitative polymerase chain reaction and western blotting. Then cell viability, apoptosis and cell invasion was measured by MTT, flow cytometry or Matrigel‑Transwell system, respectively in CRC cells after transfected with Lgr6 siRNA or Lgr6 vector. Furthermore, the expression of apoptosis‑associated protein and PI3K/AKT signaling (phosphorylated‑PI3K, phosphorylated‑AKT, t‑PI3K, t‑AKT) were measured by real‑time PCR/or western blot analysis. The results demonstrated that the level of Lgr6 was higher in CRC tissues than that in adjacent tissues, and Lgr6 overexpression increased CRC proliferation, and invasion of CRC cells in vitro. Notably, suppressing the expression of Lgr6 in CRC cells increased the expression of B‑cell lymphoma-2 (Bcl‑2)‑associated X protein and caspase‑3, but decreased the expression of Bcl‑2 at the mRNA and protein levels. Lgr6 also had the ability to regulate the phosphoinositide 3‑kinase/AKT signaling pathway. It was concluded that Lgr6 has a tumor‑promoting role in the development of CRC, and may serve as a potential diagnostic and prognostic biomarker for the disease.

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Rho GTPases as therapeutic targets in cancer (Review)

Cited by 77 publications

References 121 publications

Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

Rac1 activates non-oxidative pentose phosphate pathway to induce chemoresistance of breast cancer

Rac1/ROCK-driven membrane dynamics promote Natural Killer cell cytotoxicity via necroptosis

Downregulation of Lgr6 inhibits proliferation and invasion and increases apoptosis in human colorectal cancer

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