Expression and targeting of transcription factor <scp>ATF5</scp> in dog gliomas

York, Daniel; Sproul, Christopher D.; Chikere, N.; Dickinson, Peter J.; Angelastro, James M.

doi:10.1111/vco.12317

Cited by 13 publications

(14 citation statements)

References 37 publications

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“…Therefore, a synthetic cell-penetrating dominant negative ATF5 peptide CP-d/n-ATF5-S1 has been developed which proved activity against triple receptor negative breast cancer, prostatic carcinoma, pancreatic cancer, melanoma, non-small-cell lung carcinoma, hematological malignancies, colorectal cancer, and GBM in vitro and in six different animal models 21,22. It can be administered intraperitoneally or subcutaneously, passes the blood–brain barrier at least in mice, has cross-species efficacy, and is stable in human serum 21,22,53. This peptide significantly attenuates tumor growth in vivo by promoting apoptotic cell death of cancer cells but not of astrocytes or other cell types, thereby maintaining NB and tissue integrity 21–23…”

Section: Discussionmentioning

confidence: 99%

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients

Feldheim¹,

Keßler²,

Schmitt³

et al. 2018

OTT

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BackgroundATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.Patients and methodsATF5 mRNA was extracted from frozen samples of patients’ GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry.ResultsATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients’ age (r=0.339, P=0.028) and inversely with Ki67-staining (r=−0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan–Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t,12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084).ConclusionATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.

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Section: Discussionmentioning

confidence: 99%

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients

Feldheim¹,

Keßler²,

Schmitt³

et al. 2018

OTT

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“…Two canine glioma cells lines (J3TBG, SDT3G) were provided by UC Davis. J3TBG was derived from a grade III astrocytoma and SDT3G from a grade III glioblastoma sample ( York et al, 2018 ). The human cell line U87MG was purchased from the University of Colorado Anschutz Tissue Culture Shared Resource (PMTSR).…”

Section: Methodsmentioning

confidence: 99%

Cannabidiol Induces Apoptosis and Perturbs Mitochondrial Function in Human and Canine Glioma Cells

et al. 2021

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Cannabidiol (CBD), the major non-psychoactive compound found in cannabis, is frequently used both as a nutraceutical and therapeutic. Despite anecdotal evidence as an anticancer agent, little is known about the effect CBD has on cancer cells. Given the intractability and poor prognoses of brain cancers in human and veterinary medicine, we sought to characterize the in vitro cytotoxicity of CBD on human and canine gliomas. Glioma cells treated with CBD showed a range of cytotoxicity from 4.9 to 8.2 μg/ml; canine cells appeared to be more sensitive than human. Treatment with >5 μg/ml CBD invariably produced large cytosolic vesicles. The mode of cell death was then interrogated using pharmacologic inhibitors. Inhibition of apoptosis was sufficient to rescue CBD-mediated cytotoxicity. Inhibition of RIPK3, a classical necroptosis kinase, also rescued cells from death and prevented the formation of the large cytosolic vesicles. Next, cellular mitochondrial activity in the presence of CBD was assessed and within 2 hours of treatment CBD reduced oxygen consumption in a dose dependent manner with almost complete ablation of activity at 10 μg/ml CBD. Fluorescent imaging with a mitochondrial-specific dye revealed that the large cytosolic vesicles were, in fact, swollen mitochondria. Lastly, calcium channels were pharmacologically inhibited and the effect on cell death was determined. Inhibition of mitochondrial channel VDAC1, but not the TRPV1 channel, rescued cells from CBD-mediated cytotoxicity. These results demonstrate the cytotoxic nature of CBD in human and canine glioma cells and suggest a mechanism of action involving dysregulation of calcium homeostasis and mitochondrial activity.

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“…In addition, the UPR mt is thought to improve the survival rate of cancer cells and thus promote tumor growth[ 93 , 94 ]. ATF5 is highly expressed in undifferentiated NSCs and in a variety of human cancers, including gliomas[ 95 ]. Similarities in the expression of ATF5 in rodent, dog, and human tumors and the cross-species efficacy of the CP-d/n ATF5 peptide support the development of an ATF5-targeting approach as a novel and translational therapy for dog gliomas[ 94 ].…”

Section: Cancer Stem Cells and Mitochondria Unfolded Protein Responsementioning

confidence: 99%

Roles of mitochondrial unfolded protein response in mammalian stem cells

Gu¹,

Chen²,

Lin³

et al. 2021

WJSC

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The mitochondrial unfolded protein response (UPR mt ) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPR mt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPR mt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPR mt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPR mt in somatic cells have been widely reported, the roles of the UPR mt in stem cells are not fully understood. The roles and functions of the UPR mt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPR mt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.

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Expression and targeting of transcription factor ATF5 in dog gliomas

Abstract: Similarities in expression of ATF5 in rodent, dog and human tumours, and cross species efficacy of the CP-d/n ATF5 peptide support the development of this ATF5-targeting approach as a novel and translational therapy in dog gliomas.

Cited by 13 publications

References 37 publications

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients

Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients

Cannabidiol Induces Apoptosis and Perturbs Mitochondrial Function in Human and Canine Glioma Cells

Roles of mitochondrial unfolded protein response in mammalian stem cells

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