Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways

Sun, Guan; Shi, Lei; Li, Min; Jiang, Nan; Fu, Linshan; Guo, J.

doi:10.1016/j.jns.2014.09.034

Cited by 12 publications

(14 citation statements)

References 26 publications

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“…This is consistent with recent study that Nodal can increase the expression of Snail by activating AKT signalling and thereby repressing GSK‐3β . It has been indicated that ERK1/2 could be activated by Nodal in cancer cells, while our data revealed that Noda had no significant effect on the activation of ERK1/2 in GC cells.…”

Section: Discussioncontrasting

confidence: 69%

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Cancer‐associated fibroblasts promote malignancy of gastric cancer cells via Nodal signalling

Pang

Yin

Luo

et al. 2019

Cell Biochemistry & Function

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The roles of cancer‐associated fibroblasts (CAFs) in progression of gastric cancer (GC) are far from well illustration. Here, we show that CAFs can trigger the proliferation and decrease the doxorubicin (Dox) sensitivity of GC cells via secretion of Nodal, one embryonic morphogen that can promote malignancy of various cancers. The neutralization antibody of Nodal can attenuate CAFs‐induced cell proliferation. Further, CAFs can activate the Smad2/3 signal, which further increase the phosphorylation and nuclear localization of Akt, in GC cells. While anti‐Nodal can abolish the CAFs‐induced activation of Smad2/3/Akt signals. Further, both inhibitors of Smad2/3 and Akt can attenuate CAFs‐induced proliferation of GC cells. All these data suggest that CAFs can increase the malignancy of GC cells via Nodal‐induced activation of Smad2/3/Akt signals. It indicates that CAFs/Nodal signals might be a potential new target of clinical interventions for GC patients. Significance of the study The roles about CAFs in progression of GC are not well illustrated. Our present study reveals that CAFs can increase the proliferation and decrease the Dox sensitivity of GC cells via secretion of Nodal. The secreted Nodal further activated Samd2/3/Akt signals to trigger the GC progression. It suggests that targeted inhibition CAFs/Nodal might be a potential approach for GC therapy.

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Section: Discussioncontrasting

confidence: 69%

“…Previous study suggested that Nodal can activate the downstream signals such as Akt and ERK1/2 to promote cell proliferation . We found that rNodal can increase the phosphorylation of Akt while, not ERK1/2, in MKN‐45 cells (Figure A).…”

Section: Resultssupporting

confidence: 50%

Cancer‐associated fibroblasts promote malignancy of gastric cancer cells via Nodal signalling

Pang

Yin

Luo

et al. 2019

Cell Biochemistry & Function

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“…Inhibition of Na + /H + exchanger and cytosolic acidification parallels apoptosis [32], whereby cytosolic acidification fosters the activation of caspases [33]. Accordingly, the observed cytosolic acidification may contribute to the known stimulation of apoptosis by EA [34, 35]. …”

Section: Discussionmentioning

confidence: 99%

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

Abdelazeem

Singh

Läng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Key properties of tumor cells include enhanced glycolytic flux with excessive consumption of glucose and formation of lactate. As glycolysis is highly sensitive to cytosolic pH, maintenance of glycolysis requires export of H⁺ ions, which is in part accomplished by Na⁺/H⁺ exchangers, such as NHE1. The carrier is sensitive to oxidative stress. Growth of tumor cells could be suppressed by the polyphenol Ellagic acid, which is found in various fruits and vegetables. An effect of Ellagic acid on transport processes has, however, never been reported. The present study thus elucidated an effect of Ellagic acid on cytosolic pH (pHi), NHE1 transcript levels, NHE1 protein abundance, Na⁺/H⁺ exchanger activity, and lactate release. Methods: Experiments were performed in Ishikawa cells without or with prior Ellagic acid (20 µM) treatment. NHE1 transcript levels were determined by qRT-PCR, NHE1 protein abundance by Western blotting, pH_i utilizing (2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein [BCECF] fluorescence, Na⁺/H⁺ exchanger activity from Na⁺ dependent realkalinization after an ammonium pulse, cell volume from forward scatter in flow cytometry, reactive oxygen species (ROS) from 2’,7’-dichlorodihydrofluorescein fluorescence, glucose uptake utilizing 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose, and lactate concentration in the supernatant utilizing a colorimetric (570 nm)/ fluorometric enzymatic assay. Results: A 48 hour treatment with Ellagic acid (20 µM) significantly decreased NHE1 transcript levels by 75%, NHE1 protein abundance by 95%, pHi from 7.24 ± 0.01 to 7.02 ± 0.01, Na⁺/H⁺ exchanger activity by 77%, forward scatter by 10%, ROS by 82%, glucose uptake by 58%, and lactate release by 15%. Conclusion: Ellagic acid (20µM) markedly down-regulates ROS formation and NHE1 expression leading to decreased Na⁺/H⁺ exchanger activity, pHi, glucose uptake and lactate release in endometrial cancer cells. Those effects presumably contribute to reprogramming and growth inhibition of tumor cells.

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“…Collectively, these studies demonstrate the ability of Nodal to induce cell cycle changes and promote EMT by signaling through the ERK pathway. In support of these studies in breast cancer, overexpression of Lefty2 in glioma cells is capable of reducing signaling through ERK [116]. Additional studies addressing the upstream molecular detail of Nodal-dependent ERK activation are of interest, but the downstream molecular and functional effects of this stimulation are readily apparent.…”

Section: Nodal and Cancermentioning

confidence: 99%

Plasticity underlies tumor progression: role of Nodal signaling

Bodenstine

Chandler

Seftor

et al. 2016

Cancer Metastasis Rev

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The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its re-expression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.

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Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways

Cited by 12 publications

References 26 publications

Cancer‐associated fibroblasts promote malignancy of gastric cancer cells via Nodal signalling

Cancer‐associated fibroblasts promote malignancy of gastric cancer cells via Nodal signalling

Negative Effect of Ellagic Acid on Cytosolic pH Regulation and Glycolytic Flux in Human Endometrial Cancer Cells

Plasticity underlies tumor progression: role of Nodal signaling

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