Involvement of RalB in the effect of geranylgeranyltransferase I on glioma cell migration and invasion

Xu, Song; Liu, Hua; Xu, Yuting; Fang, Zhen; Wang, Y.; Gao, Jian; Shi, Qiong; Zhou, Xiuping; Yu, Rutong

doi:10.1007/s12094-014-1263-x

Cited by 11 publications

(4 citation statements)

References 26 publications

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“…Surprisingly, very few data exist about the importance of Ral GTPases in GBM. Our results are consistent with a previous report showing that the knockdown of RalB decreases the invasiveness of human GBM cell lines .…”

Section: Discussionsupporting

confidence: 93%

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cemeli

Guasch‐Vallés

Nàger

et al. 2019

The Journal of Pathology

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Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM.

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Section: Discussionsupporting

confidence: 93%

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cemeli

Guasch‐Vallés

Nàger

et al. 2019

The Journal of Pathology

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“…However, little is known about the role of Ral-GTPases in human malignant gliomas. The importance of geranylgeranyltransferase I (GGTase-I) in cancer progression and metastasis through membrane-targeting of Ral GTPases has been highlighted [ 20 ]. Other works have showed that overexpression of Ral-BP1 is associated with glioma grade and poor survival [ 21 ] and that Ral-BP1 knockdown reduces invasiveness, increases chemosensitivity to TMZ, and enhances the autophagy flux in these cells [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma

Cemeli

Guasch‐Vallés

Ribes-Santolaria

et al. 2022

IJMS

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Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence.

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“…RALA and RALB were shown to be involved in both mediating the inhibition of anchorage-independent growth and cell cycle progression in these cells. The importance of RALB in mediating the growth inhibition effect of GGTIs was also confirmed in other cancer types like glioma and squamous cell carcinoma (Hamada et al, 2011;Song et al, 2015). One potential problem with targeting GGTase is that many other RAS family members are also substrates for GGTase I, targeting of which might result in normal tissue toxicity.…”

Section: Targeting Ral Localizationmentioning

confidence: 84%

RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer

Yan¹,

Theodorescu²

2017

Pharmacol Rev

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More than a hundred proteins comprise the RAS superfamily of small GTPases. This family can be divided into RAS, RHO, RAB, RAN, ARF, and RAD subfamilies, with each shown to play distinct roles in human cells in both health and disease. The RAS subfamily has a well-established role in human cancer with the three genes, ,, and being the commonly mutated in tumors. These mutations, most often functionally activating, are especially common in pancreatic, lung, and colorectal cancers. Efforts to inhibit RAS and related GTPases have produced inhibitors targeting the downstream effectors of RAS signaling, including inhibitors of the RAF-mitogen-activated protein kinase/extracellular signal-related kinase (ERK)-ERK kinase pathway and the phosphoinositide-3-kinase-AKT-mTOR kinase pathway. A third effector arm of RAS signaling, mediated by RAL (RAS like) has emerged in recent years as a critical driver of RAS oncogenic signaling and has not been targeted until recently. RAL belongs to the RAS branch of the RAS superfamily and shares a high structural similarity with RAS. In human cells, there are two genes, and, both of which have been shown to play roles in the proliferation, survival, and metastasis of a variety of human cancers, including lung, colon, pancreatic, prostate, skin, and bladder cancers. In this review, we summarize the latest knowledge of RAL in the context of human cancer and the recent advancements in the development of cancer therapeutics targeting RAL small GTPases.

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Involvement of RalB in the effect of geranylgeranyltransferase I on glioma cell migration and invasion

Abstract: These findings suggest that RalB might be one of the targets for facilitating the invasive phenotype of malignant gliomas induced by GGTase-I.

Cited by 11 publications

References 26 publications

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Cytoplasmic cyclin D1 regulates glioblastoma dissemination

Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma

RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer

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