Dataset Information

Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells.

ABSTRACT: Mild hypoxia (5% O₂) as well as FGFR1-induced activation of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and MAPK signaling pathways markedly support pluripotency in human pluripotent stem cells (hPSCs). This study demonstrates that the pluripotency-promoting PI3K/AKT signaling pathway is surprisingly attenuated in mild hypoxia compared to the 21% O₂ environment. Hypoxia is known to be associated with lower levels of reactive oxygen species (ROS), which are recognized as intracellular second messengers capable of upregulating the PI3K/AKT signaling pathway. Our data denote that ROS downregulation results in pluripotency upregulation and PI3K/AKT attenuation in a hypoxia-inducible factor 1 (HIF-1)-dependent manner in hPSCs. Using specific MAPK inhibitors, we show that the MAPK pathway also downregulates ROS and therefore attenuates the PI3K/AKT signaling-this represents a novel interaction between these signaling pathways. This inhibition of ROS initiated by MEK1/2-ERK1/2 may serve as a negative feedback loop from the MAPK pathway toward FGFR1 and PI3K/AKT activation. We further describe the molecular mechanism resulting in PI3K/AKT upregulation in hPSCs-ROS inhibit the PI3K's primary antagonist PTEN and upregulate FGFR1 phosphorylation. These novel regulatory circuits utilizing ROS as second messengers may contribute to the development of enhanced cultivation and differentiation protocols for hPSCs. Since the PI3K/AKT pathway often undergoes an oncogenic transformation, our data could also provide new insights into the regulation of cancer stem cell signaling.

SUBMITTER: Fojtik P

PROVIDER: S-EPMC7859355 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells.

Fojtík Petr P Beckerová Deborah D Holomková Katerina K Šenfluk Martin M Rotrekl Vladimir V

Frontiers in cell and developmental biology 20210121

Mild hypoxia (5% O<sub>2</sub>) as well as FGFR1-induced activation of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and MAPK signaling pathways markedly support pluripotency in human pluripotent stem cells (hPSCs). This study demonstrates that the pluripotency-promoting PI3K/AKT signaling pathway is surprisingly attenuated in mild hypoxia compared to the 21% O<sub>2</sub> environment. Hypoxia is known to be associated with lower levels of reactive oxygen species (RO ...[more]

PMID: 33553145

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Project description:Bone marrow stem cells (BMSCs) have been shown to improve neurological function recovery in cerebral ischemia. Hypoxia-inducible factor-1 (HIF-1) ?-AA is a more stable mutant form of HIF-1?, which is a crucial oxygen-sensitive regulator. To investigate the protective effects of HIF-1?-AA-modified BMSCs on neuron survival in cerebral ischemia models, we co-cultured HIF-1?-AA-modified BMSCs with neuron-like cells (PC12 cells) and observed a significant increase in the release of vascular endothelial growth factor (VEGF) from BMSCs, the decreased PC12 cell apoptosis, and the upregulation of Survivin expression reduced by hypoxia in PC12 cells compared to enhanced green fluorescent protein (EGFP) BMSCs. In addition, to explore whether VEGF secreted by HIF-1?-AA-modified BMSCs plays an important role in preventing hypoxia-induced apoptosis and the possible mechanism involved, exogenous VEGF were applied and the similar protective effects on PC12 cells were observed in vitro. Furthermore, hypoxia reduced the expression of phosphorylated Akt and phosphorylated FoxO1, whereas the administration of VEGF reversed these changes. Transfection of FoxO1 H215R, a DNA-binding mutant, abrogated the inhibitory ability on Survivin promoter activity, whereas FoxO1 AAA, the active form of FoxO1, presented further repression on Survivin promoter, indicating that FoxO1 directly binds on Survivin promoter as a transcriptional repressor and that phosphorylation status of FoxO1 affects its inhibition on the Survivin promoter. Transplantation of HIF-1?-AA-modified BMSCs after cerebral ischemia in vivo sufficiently reduced neurons apoptosis, decreased cerebral infarction volume, and induced a significant improvement on the modified neurological severity score compared to the EGFP BMSCs group. In conclusion, HIF-1?-AA-modified MSCs showed an obvious protective effect on neuron-like cells or neuron after ischemia in vitro and in vivo, at least in part, through the VEGF/PI3K/Akt/FoxO1 pathway.

Project description:BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer deaths primarily due to chemoresistance. Somatic mutation of TP53 (36%) and epidermal growth factor receptor (EGFR; >?30%) are major contributors to cisplatin (CDDP) resistance. Substantial evidence suggests the elevated levels of reactive oxygen species (ROS) is a key determinant in cancer. The elevated ROS can affect the cellular responses to chemotherapeutic treatments. Although the role of EGFR in PI3K/Akt signaling cascade in NSCLC is extensively studied, the molecular link between EGFR and p53 and the role of ROS in pathogenesis of NSCLC are limitedly addressed. In this study, we investigated the role of p53 in regulation of ROS production and EGFR signaling, and the chemosensitivity of NSCLC.MethodsIn multiple NSCLC cell lines with varied p53 and EGFR status, we compared and examined the protein contents involved in EGFR-Akt-P53 signaling loop (EGFR, P-EGFR, Akt, P-Akt, p53, P-p53) by Western blot. Apoptosis was determined based on nuclear morphological assessment using Hoechst 33258 staining. Cellular ROS levels were measured by dichlorofluorescin diacetate (DCFDA) staining followed by flow cytometry analysis.ResultsWe have demonstrated for the first time that activation of p53 sensitizes chemoresistant NSCLC cells to CDDP by down-regulating EGFR signaling pathway and promoting intracellular ROS production. Likewise, blocking EGFR/PI3K/AKT signaling with PI3K inhibitor elicited a similar response. Our findings suggest that CDDP-induced apoptosis in chemosensitive NSCLC cells involves p53 activation, leading to suppressed EGFR signaling and ROS production. In contrast, in chemoresistant NSCLC, activated Akt promotes EGFR signaling by the positive feedback loop and suppresses CDDP-induced ROS production and apoptosis.ConclusionCollectively, our study reveals that the interaction of the p53 and Akt feedback loops determine the fate of NSCLC cells and their CDDP sensitivity.

Dataset Information

Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells.

Publications

Both Hypoxia-Inducible Factor 1 and MAPK Signaling Pathway Attenuate PI3K/AKT via Suppression of Reactive Oxygen Species in Human Pluripotent Stem Cells.

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