The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma

Foltyn, Martha; Luger, Anna‐Luisa; Lorenz, Nadja I.; Sauer, Benedikt; Mittelbronn, Michel; Harter, Patrick N.; Steinbach, Joachim P.; Ronellenfitsch, Michael

doi:10.1038/s41416-018-0368-3

Cited by 48 publications

(45 citation statements)

References 29 publications

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“…With demeclocycline treatment in three BTIC lines (Figure 4C). Notably, a recent study has identified that temozolomide and radiotherapy could induce DDIT4 and repressed mTORC1 activity in some glioblastoma cell lines (44). Thus, overexpression of DDIT4 by demeclocycline in BTIC could be beneficial for glioblastoma patients.…”

Section: Mechanisms Of Demeclocycline-mediated Btic Growth Reductionmentioning

confidence: 99%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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Myeloid cells that infiltrate into brain tumors are deactivated or exploited by the tumor cells. We previously demonstrated that compromised microglia, monocytes, and macrophages in malignant gliomas could be reactivated by amphotericin-B to contain the growth of brain tumorinitiating cells (BTICs). We identified meclocycline as another activator of microglia, so we sought to test whether its better-tolerated derivative, demeclocycline, also stimulates monocytes to restrict BTIC growth. Monocytes were selected for study as they would be exposed to demeclocycline in the circulation prior to entry into brain tumors to become macrophages. We found that demeclocycline increased the activity of monocytes in culture, as determined by tumor necrosis factor-α production and chemotactic capacity. The conditioned medium of demeclocycline-stimulated monocytes attenuated the growth of BTICs generated from human glioblastoma resections, as evaluated using neurosphere and alamarBlue assays, and cell counts. Demeclocycline also had direct effects in reducing BTIC growth. A global gene expression screen identified several genes, such as DNA damage inducible transcript 4, frizzled class receptor 5 and reactive oxygen species modulator 1, as potential regulators of demeclocycline-mediated BTIC growth reduction. Amongst several tetracycline derivatives, only demeclocycline directly reduced BTIC growth. In summary, we have identified demeclocycline as a novel inhibitor of the growth of BTICs, through direct effect and through indirect stimulation of monocytes. Demeclocycline is a candidate to reactivate compromised immune cells to improve the prognosis of patients with gliomas.

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Section: Mechanisms Of Demeclocycline-mediated Btic Growth Reductionmentioning

confidence: 99%

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Sarkar

Mirzaei

et al. 2020

Front. Immunol.

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“…mTORC1 multiprotein complex constitutes a major regulator of cell growth, translation, and metabolism, and has also been shown to inhibit autophagy [58,59]. Interestingly, over-expression of REDD1 in GB has been associated with resistance to temozolomide, radiotherapy, and resistance to hypoxia induced cell death, as well as linked to patient poor prognosis [60,61]. Nevertheless, the molecular mechanism(s) by which REDD1 promotes GB progression are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Investigating Glioblastoma Response to Hypoxia

et al. 2020

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Glioblastoma (GB) is the most common and deadly type of primary malignant brain tumor with an average patient survival of only 15–17 months. GBs typically have hypoxic regions associated with aggressiveness and chemoresistance. Using patient derived GB cells, we characterized how GB responds to hypoxia. We noted a hypoxia-dependent glycolytic switch characterized by the up-regulation of HK2, PFKFB3, PFKFB4, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CAIX, and SLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM, ANGPTL4, and SERPINE1/PAI-1 were up-regulated during hypoxia. We detected the hypoxic induction of invasion proteins, including the plasminogen receptor, S100A10, and the urokinase plasminogen activator receptor, uPAR. Furthermore, we observed a hypoxia-dependent up-regulation of the autophagy genes, BNIP-3 and DDIT4 and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of EGR1 and TFRC (Graphical abstract). Analysis of GB patient cohorts’ revealed differential expression of these genes in patient samples (except SLC16A3) compared to non-neoplastic brain tissue. High expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, TFRC, and ADM was associated with significantly lower overall survival. Together these data provide important information regarding GB response to hypoxia which could support the development of more effective treatments for GB patients.

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“…As we better understand the molecular mechanisms underlying glioma development, molecular targeted therapy has been proposed as a promising treatment for glioma. For instance, BRAF [35], EGFR [36], EZH2 [37], MET [38] and mTOR [39] have been reported as potential protein targets for glioma treatment. However, because of the complexity of the occurrence and development of glioma, none of these targets can completely cure glioma; thus, more novel therapeutic targets are urgently needed.…”

Section: Discussionmentioning

confidence: 99%

DGKζ Plays Crucial Roles in the Proliferation and Tumorigenicity of Human glioblastoma

Gu¹,

Wan²,

Chen³

et al. 2019

Int. J. Biol. Sci.

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Glioblastoma is one of the most malignant brain cancers in adults, and it is a fatal disease because of its untimely pathogenetic location detection, infiltrative growth, and unfavorable prognosis. Unfortunately, multimodal treatment with maximal safe resection, chemotherapy and radiation has not increased the survival rate of patients with glioblastoma. Gene-and molecular-targeted therapy is considered to be a promising anticancer strategy for glioblastoma. The identification of novel potential targets in glioblastoma is of high importance. In this study, we found that both the mRNA and protein levels of diacylglycerol kinase ζ (DGKζ) were significantly higher in glioblastoma tissues than in precancerous lesions. The silencing of DGKζ by lentivirus-delivered shRNA reduced glioblastoma cell proliferation and induced G0/G1 phase arrest. Moreover, knockdown of DGKζ expression in U251 cells markedly reduced in vitro colony formation and in vivo tumorigenic capability. Further study showed that DGKζ inhibition resulted in decreases in cyclin D1, p-AKT and p-mTOR. Moreover, the rescue or overexpression of DGKζ in glioblastoma cells demonstrated the oncogenic function of DGKζ. In conclusion, these studies suggest that the suppression of DGKζ may inhibit the tumor growth of glioblastoma cells with high DGKζ expression. Thus, DGKζ might be a potential therapeutic target in malignant glioblastoma.

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The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma

Cited by 48 publications

References 29 publications

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Demeclocycline Reduces the Growth of Human Brain Tumor-Initiating Cells: Direct Activity and Through Monocytes

Investigating Glioblastoma Response to Hypoxia

DGKζ Plays Crucial Roles in the Proliferation and Tumorigenicity of Human glioblastoma

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