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HIF-1?/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the Axin1-mediated Wnt/?-catenin signaling pathway in Parkinson's disease models.

ABSTRACT: Parkinson's disease (PD) is a progressive neurodegenerative disorder. A common and disabling disease of the elderly, the standard dopamine replacement therapies do not arrest the ongoing neurodegeneration, thus calling for new treatment strategies. The present study aimed to clarify the functional relevance of the hypoxia inducible factor-1? (HIF-1?)/microRNA-128-3p (miR-128-3p) axis in hippocampal neurodegeneration in a PD mouse model obtained by intraperitoneal injection of MPTP. Targeting relationship between miR-128-3p and Axin1 was verified, so we probed the roles of Hif1a, miR-128-3p, and Axin1 in apoptosis of hippocampal neurons with gain- and loss-of function experiments using flow cytometry and TUNEL staining. We found that Axin1 was upregulated in hippocampal tissues and cells of the MPTP-lesioned mouse model of PD, while Hif1a and miR-128-3p were downregulated. Elevation of HIF-1?/miR-128-3p inhibited apoptosis of hippocampal neurons via Wnt/?-catenin signaling pathway activation due to the suppression of Axin1 in PD. In addition, forced overexpression of Hif1a could ameliorate motor dysfunction and pathological changes in the model. Collectively, activation of the HIF-1?/miR-128-3p axis could repress hippocampal neurodegeneration in MPTP-lesioned mice through an activated Wnt/?-catenin pathway due to Axin1 downregulation.

SUBMITTER: Zhang G

PROVIDER: S-EPMC7093183 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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HIF-1α/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the <i>Axin1</i>-mediated Wnt/β-catenin signaling pathway in Parkinson's disease models.

Zhang Guangping G Chen Luzhu L Liu Jing J Jin Yan Y Lin Zaihong Z Du Shu S Fu Zenghui Z Chen Tuantuan T Qin Yinghui Y Sui Fenghu F Jiang Yan Y

Aging 20200312 5

Parkinson's disease (PD) is a progressive neurodegenerative disorder. A common and disabling disease of the elderly, the standard dopamine replacement therapies do not arrest the ongoing neurodegeneration, thus calling for new treatment strategies. The present study aimed to clarify the functional relevance of the hypoxia inducible factor-1α (HIF-1α)/microRNA-128-3p (miR-128-3p) axis in hippocampal neurodegeneration in a PD mouse model obtained by intraperitoneal injection of MPTP. Targeting rel ...[more]

PMID: 32167488

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Project description:BackgroundAcquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined.MethodsThree separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro.ResultsThe abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.ConclusionsHIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.

Project description:Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. In vitro studies suggest that flavaglines target prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. PHB1 is a highly conserved protein with diverse functions that depend on its posttranslational modifications and subcellular localization. Here, we demonstrate that FL3 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and ApcMin/+ mouse models and in human colorectal cancer tumor organoids (tumoroids) by inhibiting Wnt/β-catenin signaling via induction of Axin1 expression. FL3 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. FL3 response was diminished in colorectal cancer cell lines and human colorectal cancer tumoroids harboring a mutation at S45 of β-catenin. PHB1 deficiency in mice or in human colorectal cancer tumoroids abolished FL3-induced expression of Axin1 and drove tumoroid death. In colorectal cancer cells, FL3 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. These results suggest that FL3 inhibits Wnt/β-catenin signaling via PHB1-dependent activation of Axin1. FL3, therefore, represents a novel compound that combats Wnt pathway-dependent cancers, such as colorectal cancer. SIGNIFICANCE: Targeting of PHB1 by FL3 provides a novel mechanism to combat Wnt-driven cancers, with limited intestinal toxicity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3519/F1.large.jpg.

Dataset Information

HIF-1?/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the Axin1-mediated Wnt/?-catenin signaling pathway in Parkinson's disease models.

Publications

HIF-1α/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the <i>Axin1</i>-mediated Wnt/β-catenin signaling pathway in Parkinson's disease models.

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