MEK5/ERK5 activation regulates colon cancer stem-like cell properties

Pereira, Diane M.; Gomes, Sofia E.; Borralho, Pedro M.; Rodrigues, Cecília M. P.

doi:10.1038/s41420-019-0150-1

Cited by 37 publications

(27 citation statements)

References 78 publications

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“…First, the significant reduction in NF- κ B and P-NF- κ B expression in LPS-stimulated cells occurred after treatment with 100 μ g/ml of the extract. Pereira and colleagues showed that inhibiting ERK5 suppresses the NF- κ B signaling pathway [ 51 ]. Another study by Kloster et al reported that MEK signaling is important for activating NF- κ B signaling [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

In VitroStudies on the Immunomodulatory Effects ofPulicaria crispaExtract on Human THP-1 Monocytes

Albrahim

Alnasser

Al-Anazi

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Pulicaria crispa (P. crispa) is a plant from the Compositae family that exhibits antioxidant, anti-inflammatory, antibacterial, and cytotoxic activities. Objective. The current study aimed at investigating the immunomodulatory effects of P. crispa extract in lipopolysaccharide- (LPS-) stimulated human monocytic THP-1 cells. Methods. To induce macrophage differentiation, THP-1 cell lines were treated with phorbol-12-myristate 13-acetate, followed by exposure to LPS with or without 50 or 100 μg/ml of P. crispa extract. The following tests were employed to test the immunomodulatory effects of the extract: MTT assay, ELISA, Western blotting analysis, cell migration and phagocytosis assays, and Annexin V staining method. Results. Exposure to 100 μg/ml P. crispa extract significantly reduced THP-1 cell proliferation, migration, and phagocytosis (in LPS-stimulated cells, but not in unstimulated cells). Moreover, the extract alone significantly reduced the rate of THP-1 cell apoptosis, while it increased the rate of late apoptosis. Molecular investigations showed that treatment with P. crispa extract significantly upregulated the expression of ERK1, p-MAPK, P-P38, and Bcl2, while it significantly reduced the expression of ERK5, Bax, NF-κB, P-NF-κB, CCL1, CCL2, CCL5, CCL22, CXCL1, and CXCL10. Conclusion. Pulicaria crispa extract exhibited anti-inflammatory, antiproliferative, antimigratory, and antiphagocytic effects in LPS-stimulated THP-1 cells. Future studies should investigate these mechanisms in animal models with chronic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

In VitroStudies on the Immunomodulatory Effects ofPulicaria crispaExtract on Human THP-1 Monocytes

Albrahim

Alnasser

Al-Anazi

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Recent studies also have been demonstrated that c‐Myc can be regulated at the transcriptional level by active ERK5. Pharmacologic inhibition or siRNA silencing of ERK5 down‐regulates gene and protein expression of c‐Myc in different settings 18,31‐34 . In the present study, the pharmacologic inhibition of both ERK5 and MEK5 suppressed c‐Myc expression in macrophages upon exposure to IL‐4.…”

Section: Discussionmentioning

confidence: 46%

“…Pharmacologic inhibition or siRNA silencing of ERK5 down-regulates gene and protein expression of c-Myc in different settings. 18,[31][32][33][34] In the present study, the pharmacologic inhibition of both ERK5 and MEK5 sup- and then stimulated with IL-4 for 48 h. Arginase-1-YFP (Arg1-YFP + ) expression was assessed by flow cytometry. Data are shown as mean ± SEM (n = 4) and are representative from two independent experiments.…”

Section: Discussionmentioning

confidence: 99%

MEK5/ERK5 signaling mediates IL-4-induced M2 macrophage differentiation through regulation of c-Myc expression

Luiz

Toller-Kawahisa

Viacava

et al. 2020

Journal of Leukocyte Biology

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Macrophages are highly plastic cells, responding to diverse environmental stimuli to acquire different functional phenotypes. Signaling through MAPKs has been reported to regulate the differentiation of macrophages, but the role of ERK5 in IL-4-mediated M2 macrophage differentiation is still unclear. Here, we showed that the ERK5 signaling pathway plays a critical role in IL-4-induced M2 macrophage differentiation. Pharmacologic inhibition of MEK5, an upstream activator of ERK5, markedly reduced the expression of classical M2 markers, such as Arg-1, Ym-1, and Fizz-1, as well as the production of M2-related chemokines and cytokines, CCL22, CCL17, and IGF-1 in IL-4-stimulated macrophages. Moreover, pharmacologic inhibition of ERK5 also decreased the expression of several M2 markers induced by IL-4. In accordance, myeloid cell-specific Erk5 depletion (Erk5 ∆mye), using LysM cre /Erk5 f/f mice, confirmed the involvement of ERK5 in IL-4-induced M2 polarization. Mechanistically, the inhibition of ERK5 did not affect STAT3 or STAT6 phosphorylation, suggesting that ERK5 signaling regulates M2 differentiation in a STAT3 and STAT6independent manner. However, genetic deficiency or pharmacologic inhibition of the MEK5/ERK5 pathway reduced the expression of c-Myc in IL-4-activated macrophages, which is a critical transcription factor involved in M2 differentiation. Our study thus suggests that the MEK5/ERK5 signaling pathway is crucial in IL-4-induced M2 macrophage differentiation through the induction of c-Myc expression.

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“… 23 For example, inhibition of extracellular signal-regulated kinase 5 could eliminate cancer stem cells, thus improving colon cancer treatment. 24 Recently, through regulation of pathways involved in colon cancer stem cell, miRNAs have been reported to provide perspective on metastasis and recurrence of colon cancer. 25 Here, our results demonstrated that miR-377 could regulate cancer stem cell phenotypes, and inhibited EMT of colon cancer, suggesting that miR-377 had tumor suppressive ability against colon cancer via suppression of colon cancer stem cells and metastasis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-377 Counteracts With Cancer Stem Cell Phenotypes and Epithelial Mesenchymal Transformation by Targeting ZEB2 in Colon Cancer

Shayimu

Yusufu

Rehemutula

et al. 2020

Technol Cancer Res Treat

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Dysregulated microRNAs (miRNAs) have been implicated in the pathogenic processes of colon cancer. Epithelial mesenchymal transition (EMT) promotes metastatic progression and cancer stem cells are closely involved in colon cancer proliferation and metastasis. Functional effects of miR-377 on colon cancer stem cell phenotypes and EMT were then determined in the present study. Firstly, reduced miR-377 was found in colon cancer tissues and cell lines. Results from flow cytometry, sphere formation and western blot assays showed that miR-377 knockdown increased number of ALDH+ cells and promoted sphere formation ability. Moreover, cell migration/invasion and EMT of colon cancer cells were suppressed by miR-377 over-expression. On the contrary, miR-377 mimics caused the reversed results. ZEB2 (zinc finger E box-binding homeobox 2) was then validated as a binding target of miR-377. ZEB2 over-expression reversed the inhibitory abilities of miR-377 on cancer stem cell phenotypes, EMT, migration and invasion. In conclusion, miR-377 regulates cancer stem cell phenotypes and EMT in colon cancer cells via regulation of ZEB2, suggesting a new therapeutic strategy for colon cancer treatment.

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MEK5/ERK5 activation regulates colon cancer stem-like cell properties

Cited by 37 publications

References 78 publications

In VitroStudies on the Immunomodulatory Effects ofPulicaria crispaExtract on Human THP-1 Monocytes

In VitroStudies on the Immunomodulatory Effects ofPulicaria crispaExtract on Human THP-1 Monocytes

MEK5/ERK5 signaling mediates IL-4-induced M2 macrophage differentiation through regulation of c-Myc expression

MicroRNA-377 Counteracts With Cancer Stem Cell Phenotypes and Epithelial Mesenchymal Transformation by Targeting ZEB2 in Colon Cancer

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