Modulation of Oxidative Stress by Twist Oncoproteins

Floc’h, Nicolas; Kolodziejski, Jakub; Akkari, Leila; Simonin, Yannick; Ansieau, Stéphane; Puisieux, Alain; Hibner, Urszula; Lassus, Patrice

doi:10.1371/journal.pone.0072490

Cited by 16 publications

(10 citation statements)

References 35 publications

(55 reference statements)

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“…We also provided data indicating that TWIST2 alters the cellular redox state via a p53-dependent mechanism. These findings are consistent with a previous study showing that ectopic TWIST2 expression decreased intracellular ROS levels in human diploid fibroblasts [ 37 ]. Lastly, studies showing that FGF2-mediated induction of TWIST2 alters mitochondrial ROS generation by modulating p53 protein levels point to a novel signaling axis that may function to preserve stem cell integrity under conditions of oxidative stress.…”

Section: Discussionsupporting

confidence: 94%

Basal p53 expression is indispensable for mesenchymal stem cell integrity

et al. 2018

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Marrow-resident mesenchymal stem cells (MSCs) serve as a functional component of the perivascular niche that regulates hematopoiesis. They also represent the main source of bone formed in adult bone marrow, and their bifurcation to osteoblast and adipocyte lineages plays a key role in skeletal homeostasis and aging. Although the tumor suppressor p53 also functions in bone organogenesis, homeostasis, and neoplasia, its role in MSCs remains poorly described. Herein, we examined the normal physiological role of p53 in primary MSCs cultured under physiologic oxygen levels. Using knockout mice and gene silencing we show that p53 inactivation downregulates expression of TWIST2, which normally restrains cellular differentiation to maintain wild-type MSCs in a multipotent state, depletes mitochondrial reactive oxygen species (ROS) levels, and suppresses ROS generation and PPARG gene and protein induction in response to adipogenic stimuli. Mechanistically, this loss of adipogenic potential skews MSCs toward an osteogenic fate, which is further potentiated by TWIST2 downregulation, resulting in highly augmented osteogenic differentiation. We also show that p53−/− MSCs are defective in supporting hematopoiesis as measured in standard colony assays because of decreased secretion of various cytokines including CXCL12 and CSF1. Lastly, we show that transient exposure of wild-type MSCs to 21% oxygen upregulates p53 protein expression, resulting in increased mitochondrial ROS production and enhanced adipogenic differentiation at the expense of osteogenesis, and that treatment of cells with FGF2 mitigates these effects by inducing TWIST2. Together, these findings indicate that basal p53 levels are necessary to maintain MSC bi-potency, and oxygen-induced increases in p53 expression modulate cell fate and survival decisions. Because of the critical function of basal p53 in MSCs, our findings question the use of p53 null cell lines as MSC surrogates, and also implicate dysfunctional MSC responses in the pathophysiology of p53-related skeletal disorders.

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Section: Discussionsupporting

confidence: 94%

Basal p53 expression is indispensable for mesenchymal stem cell integrity

et al. 2018

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“…ROS are known to mediate the effects of ionizing radiation [ 25 ], and low ROS levels and radiation resistance are frequently associated in CSCs, especially in breast CSCs [ 7 , 8 ]. Twist1 and Twist2 EMT-related transcription factors are strongly overexpressed in CD24 −/low /CD44 + cells in our model (Figure 1C ) and have been reported to increase ROS scavengers and lower the level of intracellular ROS [ 26 ]. Accordingly, we clearly observed lower ROS levels in CD24 −/low /CD44 + than in CD24 + /CD44 low cells in basal non-irradiated conditions as well as in cells after irradiation.…”

Section: Discussionmentioning

confidence: 85%

Breast cancer stem cell-like cells generated during TGFβ-induced EMT are radioresistant

et al. 2018

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Failure of conventional antitumor therapy is commonly associated with cancer stem cells (CSCs), which are often defined as inherently resistant to radiation and chemotherapeutic agents. However, controversy about the mechanisms involved in the radiation response remains and the inherent intrinsic radioresistance of CSCs has also been questioned. These discrepancies observed in the literature are strongly associated with the cell models used. In order to clarify these contradictory observations, we studied the radiosensitivity of breast CSCs using purified CD24−/low/CD44+ CSCs and their corresponding CD24+/CD44low non-stem cells. These cells were generated after induction of the epithelial-mesenchymal transition (EMT) by transforming growth factor β (TGFβ) in immortalized human mammary epithelial cells (HMLE). Consequently, these 2 cellular subpopulations have an identical genetic background, their differences being related exclusively to TGFβ-induced cell reprogramming. We showed that mesenchymal CD24−/low/CD44+ CSCs are more resistant to radiation compared with CD24+/CD44low parental cells. Cell cycle distribution and free radical scavengers, but not DNA repair efficiency, appeared to be intrinsic determinants of cellular radiosensitivity. Finally, for the first time, we showed that reduced radiation-induced activation of the death receptor pathways (FasL, TRAIL and TNF-α) at the transcriptional level was a key causal event in the radioresistance of CD24−/low/CD44+ cells acquired during EMT.

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“…These data suggest that the senescence and growth arrest observed in Met −/− oval cells could be a consequence of an uncontrolled oxidative process. Interestingly, one of the key proteins that have been linked to abrogation of cellular senescence programs is Twist , which has been also described as an antioxidant factor . This prompted us to check Twist levels in our cells.…”

Section: Resultsmentioning

confidence: 99%

c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition and Regulates Cell Phenotypic Switch

et al. 2019

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Adult hepatic progenitor cells (HPCs)/oval cells are bipotential progenitors that participate in liver repair responses upon chronic injury. Recent findings highlight HPCs plasticity and importance of the HPCs niche signals to determine their fate during the regenerative process, favoring either fibrogenesis or damage resolution. Transforming growth factor-β (TGF-β) and hepatocyte growth factor (HGF) are among the key signals involved in liver regeneration and as component of HPCs niche regulates HPCs biology. Here, we characterize the TGF-β-triggered epithelialmesenchymal transition (EMT) response in oval cells, its effects on cell fate in vivo, and the regulatory effect of the HGF/c-Met signaling. Our data show that chronic treatment with TGF-β triggers a partial EMT in oval cells based on coexpression of epithelial and mesenchymal markers. The phenotypic and functional profiling indicates that TGF-β-induced EMT is not associated with stemness but rather represents a step forward along hepatic lineage. This phenotypic transition confers advantageous traits to HPCs including survival, migratory/invasive and metabolic benefit, overall enhancing the regenerative potential of oval cells upon transplantation into a carbon tetrachloride-damaged liver. We further uncover a key contribution of the HGF/c-Met pathway to modulate the TGF-β-mediated EMT response. It allows oval cells expansion after EMT by controlling oxidative stress and apoptosis, likely via Twist regulation, and it counterbalances EMT by maintaining epithelial properties. Our work provides evidence that a coordinated and balanced action of TGF-β and HGF are critical for achievement of the optimal regenerative potential of HPCs, opening new therapeutic perspectives.The findings from this study support that a balanced action of transforming growth factor-β and hepatocyte growth factor could determine liver progenitor's fate and the outcome of liver regeneration, and open possibilities for targeted therapies oriented at improving the regenerative capacity of these cells in chronic liver diseases.

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Modulation of Oxidative Stress by Twist Oncoproteins

Cited by 16 publications

References 35 publications

Basal p53 expression is indispensable for mesenchymal stem cell integrity

Basal p53 expression is indispensable for mesenchymal stem cell integrity

Breast cancer stem cell-like cells generated during TGFβ-induced EMT are radioresistant

c-Met Signaling Is Essential for Mouse Adult Liver Progenitor Cells Expansion After Transforming Growth Factor-β-Induced Epithelial–Mesenchymal Transition and Regulates Cell Phenotypic Switch

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