GPD1 Specifically Marks Dormant Glioma Stem Cells with a Distinct Metabolic Profile

Rusu, Patricia M.; Shao, Chunxuan; Neuerburg, Anna; Açıkgöz, Azer Aylin; Wu, Yonghe; Zou, Peng; Phapale, Prasad; Shankar, Tchirupura S.; Döring, Kristina; Dettling, Steffen; Körkel-Qu, Huiqin; Bekki, Gözde; Costa, Bárbara; Guo, Te; Friesen, Olga; Schlotter, Magdalena; Heikenwälder, Mathias; Tschaharganeh, Darjus F.; Bukau, Bernd; Krämer, Günter; Angel, Peter; Herold‐Mende, Christel; Radlwimmer, Bernhard; Liu, Hai-Kun

doi:10.1016/j.stem.2019.06.004

Cited by 79 publications

(67 citation statements)

References 74 publications

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“…These studies were consistent with our results that GPD1 overexpression may inhibit cancer cell growth. However, specific expression of GPD1 was observed in brain tumor stem cells and involved in tumor initiation (8). Our RNA sequencing results suggested many cellular signaling pathways and metabolic pathways can be regulated by GPD1, but these pathways were apparently different between cancer types.…”

Section: Discussionmentioning

confidence: 77%

“…Another study demonstrated that lack of GPD1 inhibits gluconeogenesis by suppressing glycerol conversion at the primary stage of fasting and eventually induces a higher concentration of blood glucose in a sustained fasting condition (5). Besides, GPD1 was suggested to exert an anti-tumor effect in breast cancer (6,7), whereas it can promote the progression of glioblastoma (8). However, previous studies demonstrated that GPDH shows an extremely low expression level or absent in some tumor tissues (9,10).…”

Section: Introductionmentioning

confidence: 99%

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GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate

Xie

Cai

et al. 2020

Cancer Research

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Metformin is an oral drug widely used for the treatment of type 2 diabetes mellitus. Numerous studies have demonstrated the value of metformin in cancer treatment. However, for metformin to elicit effects on cancer this often requires a high dosage, and any underlying mechanism for how to improve its inhibitory effects remains unknown. Here we found that low mRNA expression of glycerol-3-phosphate dehydrogenase 1 (GPD1) may predict a poor response to metformin treatment in 15 cancer cell lines. In vitro and in vivo, metformin treatment alone significantly suppressed cancer cell proliferation, a phenotype enhanced by GPD1 overexpression. Total cellular glycerol-3-phosphate concentration was significantly increased by the combination of GPD1 overexpression and metformin treatment, which suppressed cancer growth via inhibition of mitochondrial function. Eventually, increased reactive oxygen species and mitochondrial structural damage was observed in GPD1-overexpressing cell lines treated with metformin, which may contribute to cell death. In summary, this study demonstrates that GPD1 overexpression enhances the anti-cancer activity of metformin and that patients with increased GPD1 expression in tumor cells may respond better to metformin therapy. SignificanceGPD1 overexpression enhances the anti-cancer effect of metformin through synergistic inhibition of mitochondrial function, thereby providing new insight into metformin-mediated cancer therapy.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate

Xie

Cai

et al. 2020

Cancer Research

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“…These results confirmed that the migration ability of GSC was significantly reduced after the hub gene was knocked down. As a key molecule to maintain the stemness of tumor cells, CD133 is a common surface marker in stem cells or progenitor cells, especially in the nervous system (Wilson et al, 2004;Rusu et al, 2019). We examined the ratio of CD133 in stem cells with different shRNAs by flow cytometry.…”

Section: Knockdown Of the Hub Proteinsmentioning

confidence: 99%

Identification of Prognostic Model and Biomarkers for Cancer Stem Cell Characteristics in Glioblastoma by Network Analysis of Multi-Omics Data and Stemness Indices

Yan

et al. 2020

Front. Cell Dev. Biol.

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The progression of most human cancers mainly involves the gradual accumulation of the loss of differentiated phenotypes and the sequential acquisition of progenitor and stem cell-like features. Glioblastoma multiforme (GBM) stem cells (GSCs), characterized by self-renewal and therapeutic resistance, play vital roles in GBM. However, a comprehensive understanding of GBM stemness remains elusive. Two stemness indices, mRNAsi and EREG-mRNAsi, were employed to comprehensively analyze GBM stemness. We observed that mRNAsi was significantly related to multi-omics parameters (such as mutant status, sample type, transcriptomics, and molecular subtype). Moreover, potential mechanisms and candidate compounds targeting the GBM stemness signature were illuminated. By combining weighted gene co-expression network analysis with differential analysis, we obtained 18 stemness-related genes, 10 of which were significantly related to survival. Moreover, we obtained a prediction model from both two independent cancer databases that was not only an independent clinical outcome predictor but could also accurately predict the clinical parameters of GBM. Survival analysis and experimental data confirmed that the five hub genes (CHI3L2, FSTL3, RPA3, RRM2, and YTHDF2) could be used as markers for poor prognosis of GBM. Mechanistically, the effect of inhibiting the proliferation of GSCs was attributed to the reduction of the ratio of CD133 and the suppression of the invasiveness of GSCs. The results based on an in vivo xenograft model are consistent with the finding that knockdown of the hub gene inhibits the growth of GSCs in vitro. Our approach could be applied to facilitate the development of objective diagnostic and targeted treatment tools

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“…Therefore, in a dormant system, the reduction of ROS can be successfully achieved through the dampening of the metabolic rate and through an efficient OXPHOS. Similarly, dormant glioma stem cells were proven to shunt glycolytic intermediates towards glycerol and phospholipid metabolism via the upregulation of the enzyme GPD1: this metabolic profile is crucial to withstand ROS and ultimately maintain the dormant compartment of glioma cells [211]. ROS withstanding was shown to be critical also in in vitro models of dormant breast cancer, where a generally slower metabolism is associated with glycolytic downregulation and nicotinamide synthesis upregulation: ROS detoxification is achieved here through the increased production of NADH and NADPH [212].…”

Section: Metabolic Features Of In Situ and Metastatic Dormant Cancer mentioning

confidence: 99%

Metabolic Constrains Rule Metastasis Progression

Roda

Gambino

2020

Cells

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Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression.

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GPD1 Specifically Marks Dormant Glioma Stem Cells with a Distinct Metabolic Profile

Cited by 79 publications

References 74 publications

GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate

GPD1 Enhances the Anticancer Effects of Metformin by Synergistically Increasing Total Cellular Glycerol-3-Phosphate

Identification of Prognostic Model and Biomarkers for Cancer Stem Cell Characteristics in Glioblastoma by Network Analysis of Multi-Omics Data and Stemness Indices

Metabolic Constrains Rule Metastasis Progression

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