Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

Silva, Patricio; Soto, Nicolás Ried; Díaz, Jorge; Mendoza, Pablo; Díaz, Nora; Quest, Andrew F. G.; Torres, Vicente A.

doi:10.1016/j.bbrc.2015.06.176

Cited by 5 publications

(5 citation statements)

References 27 publications

(35 reference statements)

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“…It should be noted that for most studies, A549 cells were used, because these cells were suitable for down-regulation experiments with different shRNA sequences and for transfection experiments with shRNA-resistant Rab5 mutants. Rab5 down-regulation with different shRNA sequences was previously described [ 20 , 39 ]. Control cells were infected with a lentivirus encoding a nonspecific shRNA sequence (plasmid 1864; Addgene, Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

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Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis

et al. 2016

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Hypoxia, a common condition of the tumor microenvironment, is associated with poor patient prognosis, tumor cell migration, invasion and metastasis. Recent evidence suggests that hypoxia alters endosome dynamics in tumor cells, leading to augmented cell proliferation and migration and this is particularly relevant, because endosomal components have been shown to be deregulated in cancer. The early endosome protein Rab5 is a small GTPase that promotes integrin trafficking, focal adhesion turnover, Rac1 activation, tumor cell migration and invasion. However, the role of Rab5 and downstream events in hypoxia remain unknown. Here, we identify Rab5 as a critical player in hypoxia-driven tumor cell migration, invasion and metastasis. Exposure of A549 human lung carcinoma, ZR-75, MDA-MB-231 and MCF-7 human breast cancer and B16-F10 mouse melanoma cells to hypoxia increased Rab5 activation, followed by its re-localization to the leading edge and association with focal adhesions. Importantly, Rab5 was required for hypoxia-driven cell migration, FAK phosphorylation and Rac1 activation, as shown by shRNA-targeting and transfection assays with Rab5 mutants. Intriguingly, the effect of hypoxia on both Rab5 activity and migration was substantially higher in metastatic B16-F10 cells than in poorly invasive B16-F0 cells. Furthermore, exogenous expression of Rab5 in B16-F0 cells predisposed to hypoxia-induced migration, whereas expression of the inactive mutant Rab5/S34N prevented the migration of B16-F10 cells induced by hypoxia. Finally, using an in vivo syngenic C57BL/6 mouse model, Rab5 expression was shown to be required for hypoxia-induced metastasis. In summary, these findings identify Rab5 as a key mediator of hypoxia-induced tumor cell migration, invasion and metastasis.

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Section: Methodsmentioning

confidence: 99%

“…Measurements were performed as previously described [ 39 ], but important modifications were included. First, experiments were performed in the presence of serum, and second, measurements were done for up to 24 h. MTS assay .…”

Section: Methodsmentioning

confidence: 99%

Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis

et al. 2016

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“…Rab5 has been found to be upregulated in many cancers including colorectal cancer [84], breast cancer [75,85], cervical cancer [86], liver cancer [82], lung cancer [87] and pancreatic cancer [88,89]. Overexpression of RAB5A is an indicator of poor prognosis in hepatocellular carcinoma, pancreatic cancer and estrogen receptor positive breast cancer [86,90,91,92]. These studies demonstrated that migration and invasion of cancer cells are directly affected by Rab5 expression levels.…”

Section: Small Gtpases–p85α Interactions and Alterationsmentioning

confidence: 99%

Impact of p85α Alterations in Cancer

et al. 2019

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The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in the regulation of cell signaling, proliferation, survival, migration and vesicle trafficking in normal cells and is frequently deregulated in many cancers. The p85α protein is the most characterized regulatory subunit of the class IA PI3Ks, best known for its regulation of the p110-PI3K catalytic subunit. In this review, we will discuss the impact of p85α mutations or alterations in expression levels on the proteins p85α is known to bind and regulate. We will focus on alterations within the N-terminal half of p85α that primarily regulate Rab5 and some members of the Rho-family of GTPases, as well as those that regulate PTEN (phosphatase and tensin homologue deleted on chromosome 10), the enzyme that directly counteracts PI3K signaling. We highlight recent data, mapping the interaction surfaces of the PTEN–p85α breakpoint cluster region homology (BH) domain, which sheds new light on key residues in both proteins. As a multifunctional protein that binds and regulates many different proteins, p85α mutations at different sites have different impacts in cancer and would necessarily require distinct treatment strategies to be effective.

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“…[17][18][19][20][21] Specifically, within the family of Rab GTPases, which control endocytic trafficking, Rab5 has been reported to be upregulated in different cancers, including lung adenocarcinoma, 22 pancreatic cancer, 23 ovarian cancer, 24 hepatocellular carcinoma, 25 and OSCC. 18 Rab5 is a small GTPase that controls early endosome dynamics, 26 which has been shown by us and others, to promote the acquisition of different malignant traits, including cell migration and invasion, [27][28][29][30] the epithelial to mesenchymal transition, 23 tumorigenesis in vivo, 31 and metastasis in vivo. 27,30 Intriguingly, Rab5 was recently shown to be upregulated in OSCC and associated with malignant traits in this malignancy, 18 however several issues emerge from these findings.…”

Section: Introductionmentioning

confidence: 99%

“…Rab5 is a small GTPase that controls early endosome dynamics, which has been shown by us and others, to promote the acquisition of different malignant traits, including cell migration and invasion, the epithelial to mesenchymal transition, tumorigenesis in vivo, and metastasis in vivo . Intriguingly, Rab5 was recently shown to be upregulated in OSCC and associated with malignant traits in this malignancy, however several issues emerge from these findings.…”

Section: Introductionmentioning

confidence: 99%

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

et al. 2020

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Potentially malignant lesions, commonly referred to as dysplasia, are associated with malignant transformation by mechanisms that remain unclear. We recently reported that increased Wnt secretion promotes the nuclear accumulation of β‐catenin and expression of target genes in oral dysplasia. However, the mechanisms accounting for nuclear re‐localization of β‐catenin in oral dysplasia remain unclear. In this study, we show that endosomal sequestration of the β‐catenin destruction complex allows nuclear accumulation of β‐catenin in oral dysplasia, and that these events depended on the endocytic protein Rab5. Tissue immunofluorescence analysis showed aberrant accumulation of enlarged early endosomes in oral dysplasia biopsies, when compared with healthy oral mucosa. These observations were confirmed in cell culture models, by comparing dysplastic oral keratinocytes (DOK) and non‐dysplastic oral keratinocytes (OKF6). Intriguingly, DOK depicted higher levels of active Rab5, a critical regulator of early endosomes, when compared with OKF6. Increased Rab5 activity in DOK was necessary for nuclear localization of β‐catenin and Tcf/Lef‐dependent transcription, as shown by expression of dominant negative and constitutively active mutants of Rab5, along with immunofluorescence, subcellular fractionation, transcription, and protease protection assays. Mechanistically, elevated Rab5 activity in DOK accounted for endosomal sequestration of components of the destruction complex, including GSK3β, Axin, and adenomatous polyposis coli (APC), as observed in Rab5 dominant negative experiments. In agreement with these in vitro observations, tissue immunofluorescence analysis showed increased co‐localization of GSK3β, APC, and Axin, with early endosome antigen 1‐ and Rab5‐positive early endosomes in clinical samples of oral dysplasia. Collectively, these data indicate that increased Rab5 activity and endosomal sequestration of the β‐catenin destruction complex leads to stabilization and nuclear accumulation of β‐catenin in oral dysplasia.

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Down-regulation of Rab5 decreases characteristics associated with maintenance of cell transformation

Cited by 5 publications

References 27 publications

Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis

Hypoxia promotes Rab5 activation, leading to tumor cell migration, invasion and metastasis

Impact of p85α Alterations in Cancer

Nuclear accumulation of β‐catenin is associated with endosomal sequestration of the destruction complex and increased activation of Rab5 in oral dysplasia

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