KDELR2 Promotes Glioblastoma Tumorigenesis Targeted by HIF1a via mTOR Signaling Pathway

Liao, Zhangyuan; Chen, She; Ma, Li; Sun, Zengfeng; Zhang, Xiaohui; Wang, Peng; Li, Wenliang

doi:10.1007/s10571-019-00715-2

Cited by 23 publications

(26 citation statements)

References 26 publications

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“…Colorectal cancer, gliomas, and melanoma have also been linked with increased KDEL receptor expression ( Table 1 [ 56 , 58 , 59 , 60 ]). In particular, KDELR2 upregulation has been associated with poor outcomes, perhaps because of the role KDELR2 may play in promoting cell proliferation through the mTORC1 pathway [ 61 , 75 ]. Furthermore, tumorigenic cells have an increased demand for protein synthesis in order to support tumor proliferation, migration, and differentiation.…”

Section: Kdel Receptors Upr and Diseasementioning

confidence: 99%

The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein misfolding and activation of the unfolded protein response (UPR). Additionally, ER resident proteins are secreted from the cell by overwhelming the KDEL receptor retrieval pathway. Recent data show that KDEL receptors are also activated during the UPR through the IRE1/XBP1 signaling pathway as an adaptive response to cellular stress set forth to reduce the loss of ER resident proteins. This review will discuss the emerging connection between UPR activation and KDEL receptors as it pertains to ER proteostasis and disease states.

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Section: Kdel Receptors Upr and Diseasementioning

confidence: 99%

The Function of KDEL Receptors as UPR Genes in Disease

Wires

Kennedy

Harvey

2021

IJMS

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“…As previously reported, KDELR knockdown attenuated the anti-apoptotic effects of Santacruzamate A in the pathophysiology of Alzheimer's disease (35), and KDELR2 knockdown reduced cell viability and inhibited colony formation in glioblastoma cells (30). To measure the effect of KDELR2 knockdown in glioma cells, we established KDELR2 knockdown U373 cells with siRNAs (siKDELR2#1, siKDELR2#2, and siKDELR2#3) evaluated them by RT-qPCR (Figure 2A) and western blot analysis (Figure 2B).…”

Section: Kdelr2 Knockdown Inhibits Cell Proliferation and Induces Cell Apoptosis In Gliomamentioning

confidence: 79%

“…The functions of KDELRs are associated with cancer biology (19,(27)(28)(29)(30), especially in glioma: KDELR1 can significantly reduce the expression of the ER transcription factor CREB3 (27) and block hypoxia-induced autophagy in glioblastoma (28); KDELR2 has been associated with the median survival rate of non-small cell lung cancer (29), and it promotes glioblastoma tumorigenesis, which is regulated by hypoxia-inducible factor 1 (HIF-1) (30). Knockdown of KDELR2 has been shown to reduce cell viability, promote cell cycle arrest, and induce apoptotic cell death by targeting cell cycle proteins (31) In addition, KDELR3 promotes high melanoma metastasis (19).…”

Section: Introductionmentioning

confidence: 99%

KDELR2 knockdown synergizes with temozolomide to induce glioma cell apoptosis through the CHOP and JNK/p38 pathways

Wang¹,

Cheng²,

Fan³

et al. 2021

Transl Cancer Res TCR

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Background: The C-terminal tetrapeptide Lys-Asp-Glu-Leu receptors (KDELRs) are transmembrane proteins that regulate ER stress (ERS) response, growth, differentiation, and immune responses. There is an association between KDELR2and promotion of glioblastoma tumorigenesis. The aim of the present study was to explore the functional mechanism of KDELR2 in glioma and during response to chemotherapy to temozolomide (TMZ).Methods: The expression of KDELR2 in glioma tissues and cells was evaluated by immunohistochemistry, western blot and RT-qPCR assay. Then role of KDELR2 was demonstrated by CCK8, colony formation, flow cytometry and Hochest 33258 assays. The expression of genes (ATF4, ATF6, PERK, eIF2-α, GRP78 and CHOP) in U373 cells was evaluated by RT-qPCR. The protein expression of genes (cleaved caspase 3, caspase 3, cleaved PARP, PARP, Bax, Bcl-2, JNK, p-JNK, p38, p-p38, ATF4, ATF6, XBP-1s, PERK, p-PERK, GRP78 and CHOP) was measured by western blot assay.Results: The expression of KDELR2 was upregulated in high-grade gliomas tissues. KDELR2 knockdown suppressed cell proliferation but increased cell apoptosis. Further, Knockdown of KDELR2 also activated the ER stress (ERS)-dependent CHOP pathway, and resulted in increased levels of phosphorylated c-Jun N-terminal kinase (JNK) and p38. Moreover, the combination of KDELR2 knockdown and TMZ application showed a synergistic cytotoxic effect in U373 cells through the ERS-dependent CHOP and JNK/p38 pathways.Conclusions: KDELR2 knockdown induces apoptosis and sensitizes glioma cells to TMZ, which is mediated by the ERS-dependent CHOP and JNK/p38 pathways.

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“…5B). HiF1α is a critical protein regulated by aKT1/mTor; increased levels of HiF1α translocate to the nucleus to promote various cancer cell processes, such as proliferation and migration (15). Therefore, the expression of HiF1α was investigated; the expression levels of HiF1α were also decreased when clec3a was knocked down compared to the nc group (Fig.…”

Section: (µM) -------------------------------------------------mentioning

confidence: 99%

Suppression of CLEC3A inhibits osteosarcoma cell proliferation and promotes their chemosensitivity through the AKT1/mTOR/HIF1α signaling pathway

Ren¹,

Pan²,

Hou³

et al. 2020

Mol Med Report

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osteosarcoma (oS) is a primary malignant tumor that occurs in bone, and mainly affects children and adolescents. c-type lectin domain family 3 member a (clec3a) is a member of the c-type lectin superfamily, which regulates various biological functions of cells. The present study aimed to identify the effects and related mechanisms of clec3a in the proliferation and chemosensitivity of oS cells. The expression of clec3a in oS was analyzed using the Gene Expression Omnibus data profile GSE99671, and its expression in OS samples was verified using reverse transcription-quantitative PCR (RT-qPCR) and immunohistochemical staining. The relationship between the expression of clec3a and clinical traits in patients with oS was also analyzed, including age, tumor size, TnM stage and lymph node metastasis. cell counting Kit-8 assays, colony formation assays and cell cycle distribution analysis were used to determine the roles of clec3a in the proliferation and chemosensitivity of OS cells. Finally, RT-qPCR and western blotting were used to demonstrate the relationship between clec3a and the aKT1/mTor/hypoxia-inducible factor 1-α (HiF1α) pathway. Both the mrna and protein expression levels of clec3a were increased in oS tissues compared with adjacent non-tumor tissues, and this was positively associated with TnM stage and lymph node metastasis. The genetic knockdown of clec3a with small interfering rna decreased oS cell proliferation and colony formation, and induced G1 phase arrest, whereas the overexpression of clec3a increased oS cell proliferation and colony formation, and alleviated G1 phase arrest. The suppression of clec3a also promoted enhanced the chemosensitivity of oS cells to doxorubicin (doX) and cisplatin (cddP); it also inhibited the expression of aKT1, mTor and HiF1α, further to the nuclear localization of HiF1α, and HiF1α target gene expression levels, including VeGF, GluT1 and Mcl1 were also decreased. Furthermore, treatment with the aKT activator Sc79 blocked the inhibitory effects of clec3a silencing in oS cells. in conclusion, these findings suggested that CLEC3A may function as an oncogene in oS, and that the suppression of clec3a may inhibit oS cell proliferation and promote chemosensitivity through the aKT1/mTor/HiF1α signaling pathway.

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KDELR2 Promotes Glioblastoma Tumorigenesis Targeted by HIF1a via mTOR Signaling Pathway

Cited by 23 publications

References 26 publications

The Function of KDEL Receptors as UPR Genes in Disease

The Function of KDEL Receptors as UPR Genes in Disease

KDELR2 knockdown synergizes with temozolomide to induce glioma cell apoptosis through the CHOP and JNK/p38 pathways

Suppression of CLEC3A inhibits osteosarcoma cell proliferation and promotes their chemosensitivity through the AKT1/mTOR/HIF1α signaling pathway

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