XBP1 silencing decreases glioma cell viability and glycolysis possibly by inhibiting HK2 expression

Liu, Yaohua; Hou, Xu; Liu, Min; Zhong, Yang; Bi, Yunke; Zou, Huichao; Wu, Jianing; Che, Hui; Li, Chenguang; Wang, Xiaoxiong; Chen, Zhong; Zhang, Jiakang; Yu, Tao; Bian, Qilong; Chai, Shuang; Liu, Huailei; Ai, Jing

doi:10.1007/s11060-015-2003-y

Cited by 20 publications

(13 citation statements)

References 27 publications

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“…Specifically, our data imply a more prominent role for XBP1 in the regulation and process of glycolysis. This finding is in line with a recent report demonstrating that silencing XBP1 in glioma cells inhibits glycolysis resulting in reduced ATP production and decreased cancer cell survival [ 26 ]. Long-term activation of the IRE1 signaling has also been shown to reduce glucose metabolism and mitochondrial function; however, it is unclear whether this effect is mediated by XBP1 [ 27 ].…”

Section: Discussionsupporting

confidence: 92%

Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

McLaughlin

Falkowski

Park

et al. 2018

Mol Neurodegeneration

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BackgroundAging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses. Herein, we investigate the role of XBP1 in maintaining morphological and functional integrity in retinal neurons during adulthood and the early stages of aging.MethodsThe basal and induced levels of XBP1 activation in the retina were measured in young adult and aged mice. Conditional knockout (cKO) of XBP1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina specific Cre-recombinase line (Chx10-Cre). Retinal morphology, neuronal populations including photoreceptors, bipolar cells, and retinal ganglion cells (RGCs), synaptic structure, and microglial activation were examined with immunohistochemistry and staining of retinal sections. Retinal function was evaluated with light-adapted (photopic) and dark adapted (scotopic) electroretinograms. Retinal mitochondrial function and metabolism was assessed by Seahorse XFe24 Extracellular Flux Analyzer.ResultsThe retinas of aged wild type (WT) mice display a significantly reduced basal level of Xbp1s and compromised activation of ER stress response. In XBP1 cKO mice, significant structural degeneration of the retina, evidenced by thinning of retinal layers and a loss of RGCs, and functional defects indicated by diminished photopic and scotopic ERG b-waves are observed at the age of 12–14 months. Furthermore, discontinuous and disorganized synaptic laminae, colocalized with activated microglia, in the inner plexiform layer is found in the XBP1 cKO retinas. In addition, cKO mice demonstrate a significant increase in ectopic synapses between bipolar cells and photoreceptors, which is strikingly similar to WT mice at 20–24 months of age. These changes are associated with defective retinal glycolysis while mitochondrial respiratory function appears normal in the cKO retina.ConclusionsXBP1 cKO mice at 12–14 months of age show significant structural, functional, and metabolic deficits that closely resemble WT mice twice that age. Our findings suggest that the absence of XBP1, a critical component of the UPR, accelerates age-related retinal neurodegeneration.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0250-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

McLaughlin

Falkowski

Park

et al. 2018

Mol Neurodegeneration

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“…Importantly, splicing and activation of XBP1 and its complex formation with HIF-1α was recently shown to enhance a hypoxic phenotype and subsequently promote the progression of triple negative breast cancers 45 . The XBP1/HIF-1α complex binds to and regulates genes associated with the Warburg phenotype 45 , and XBP1 silencing abrogates the glycolytic phenotype of gliomas 89 . We have shown previously that adipocytes promote oxygen-independent HIF-1α activation in prostate cancer cells and that HIF-1α signaling is responsible for adipocyte-induced glycolytic phenotype 6 .…”

Section: Discussionmentioning

confidence: 99%

Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin

Herroon

Rajagurubandara

Diedrich

et al. 2018

Sci Rep

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Metastatic tumor cells engage the local tumor microenvironment and activate specific pro-survival mechanisms to thrive and progress in the harsh bone marrow niche. Here we show that the major contributors to the survival of carcinoma cells that have colonized the bone marrow are the adipocyte-induced oxidative stress and ER stress pathways. We demonstrate that upon exposure to adipocyte-rich environments in vitro or in vivo, bone-trophic prostate and breast tumor cells upregulate the oxidative stress enzyme, HO-1. We also show that HO-1 levels are significantly increased in human metastatic prostate cancer tissues and that stable HO-1 overexpression in tumor cells promotes growth and invasiveness. Co-incident with the adipocyte-induced expression of HO-1, there is an upregulation of ER chaperone BIP and splicing of XBP1, indicating adipocyte-driven unfolded protein response, a process that we show to be sensitive to antioxidant treatment. Importantly, we also demonstrate that triggering of the oxidative stress and ER stress responses, or HO-1 induction by adipocyte exposure result in the activation of pro-survival pathways, involving survivin. Collectively, our findings reveal a new link between HO-1 and survivin expression in tumor cells, and provide a new insight into potentially targetable survival pathways in bone-metastatic disease.

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“…25 In contrast, XBP1 silenced glioma cells showed a decreased capacity of tumor formation. 29 Moreover, several studies demonstrated that the knock-down of XBP1 gene expression promotes impairment of tumor growth and tumor cell invasion. 24,30 Similarly, low expression of UPR including (XBP1) in PCa may permit cancer cells to escape apoptosis and support tumorgenesis.…”

Section: Discussionmentioning

confidence: 99%

Unique expression of the xbp1 gene correlates with human prostate cancer

Khalil¹

2017

JIG

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All participants provided verbal informed consents for the use of their tissue samples. Forty five formalinfixed paraffin embedded (FFPE) tissue blocks without cut faces were used in this study tominimize possible damage from exposure to atmospheric oxygen, water, and other environmental factors such as light and infestation (fungus, insects, etc.). The blocks were divided into three groups: thirty contained prostate malignant tissues; ten had benign prostate tissues and five with normal prostate tissues. The PCa samples were obtained from patients who underwent radical

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XBP1 silencing decreases glioma cell viability and glycolysis possibly by inhibiting HK2 expression

Cited by 20 publications

References 27 publications

Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration

Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin

Unique expression of the xbp1 gene correlates with human prostate cancer

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