The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes

Xing, Fan; Luan, Yizhao; Cai, Jing; Wu, Sihan; Mai, Jialuo; Gu, Jiayu; Zhang, Haipeng; Li, Kai; Lin, Yongcheng; Xiao, Xiao; Liang, Jiankai; Li, Yuan; Chen, Wenli; Tan, Yaqian; Sheng, Longxiang; Lu, Bingzheng; Lu, Wanjun; Gao, Mingshi; Qiu, Pengxin; Su, Xingwen; Yin, Wei; Hu, Jun; Chen, Zhongping; Sai, Ke; Wang, Jing; Chen, Fu‐Rong; Chen, Yinsheng; Zhu, Shida; Liu, Dongbing; Cheng, Shi‐Yuan; Xie, Zhi; Zhu, Wenbo; Gao, Yan

doi:10.1016/j.celrep.2016.12.037

Cited by 88 publications

(73 citation statements)

References 45 publications

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“…, ; Xing al. , ), and we used it as a differentiation inducer in our research. In contrast with the mainly flattened and polygonal shape of the control cells, the morphology of the dbcAMP‐treated DBTRG‐05MG cells resembled that of mature neural cells, with smaller, round cell bodies and longer processes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Negative regulation of miR‐1275 by H3K27me3 is critical for glial induction of glioblastoma cells

Mai

Liu

et al. 2019

Molecular Oncology

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Activation of the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway induces glial differentiation of glioblastoma (GBM) cells, but the mechanism by which microRNA (miRNA) regulate this process remains poorly understood. In this study, by performing miRNA genomics and loss‐ and gain‐of‐function assays in dibutyryl‐cAMP‐treated GBM cells, we identified a critical negative regulator, hsa‐miR‐1275, that modulates a set of genes involved in cancer progression, stem cell maintenance, and cell maturation and differentiation. Additionally, we confirmed that miR‐1275 directly and negatively regulates the protein expression of glial fibrillary acidic protein (GFAP), a marker of mature astrocytes. Of note, tri‐methyl‐histone H3 (Lys27) (H3K27me3), downstream of the PKA/polycomb repressive complex 2 (PRC2) pathway, accounts for the downregulation of miR‐1275. Furthermore, decreased miR‐1275 expression and induction of GFAP expression were also observed in dibutyryl‐cAMP‐treated primary cultured GBM cells. In a patient‐derived glioma stem cell tumor model, a cAMP elevator and an inhibitor of H3K27me3 methyltransferase inhibited tumor growth, induced differentiation, and reduced expression of miR‐1275. In summary, our study shows that epigenetic inhibition of miR‐1275 by the cAMP/PKA/PRC2/H3K27me3 pathway mediates glial induction of GBM cells, providing a new mechanism and novel targets for differentiation‐inducing therapy.

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Section: Resultsmentioning

confidence: 99%

Negative regulation of miR‐1275 by H3K27me3 is critical for glial induction of glioblastoma cells

Mai

Liu

et al. 2019

Molecular Oncology

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“…With regard to cellular metabolism it is important to note that GBM displays a unique bioenergetic state of aerobic glycolysis known as the “Warburg effect” 53 , 54 . Accordingly, reports have emerged which have come to suggest that targeting the Warburg shift may represent a novel therapeutic approach for the treatment of GBM 55 – 57 . Again, both SUMOylation and HIF-1α have been shown to play definite roles in a switch to glycolysis in states of both health and disease 29 , 30 , 58 , 59 .…”

Section: Discussionmentioning

confidence: 99%

Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming

Bernstock

Geßler

et al. 2017

Sci Rep

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Protein SUMOylation is a dynamic post-translational modification shown to be involved in a diverse set of physiologic processes throughout the cell. SUMOylation has also been shown to play a role in the pathobiology of myriad cancers, one of which is glioblastoma multiforme (GBM). As such, the clinical significance and therapeutic utility offered via the selective control of global SUMOylation is readily apparent. There are, however, relatively few known/effective inhibitors of global SUMO-conjugation. Herein we describe the identification of topotecan as a novel inhibitor of global SUMOylation. We also provide evidence that inhibition of SUMOylation by topotecan is associated with reduced levels of CDK6 and HIF-1α, as well as pronounced changes in cell cycle progression and cellular metabolism, thereby highlighting its putative role as an adjuvant therapy in defined GBM patient populations.

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“…It has also been proposed that mitochondrially induced apoptosis can be induced indirectly, via Ca 2+ overload [93] or proteasome inhibition [103]. Finally, there is evidence that mitochondrial biogenesis induced by activation of cAMP-mediated signaling can reduce malignancy of GBM cells [104].…”

Section: Are Mitochondria a Possible "Weak Spot" Of Glioblastoma Multmentioning

confidence: 99%

“…(2) Dibutyryl-cAMP (dbcAMP) activates phosphoprotein kinase A and across cAMP response element-binding protein (CREB protein) activates the synthesis of Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) protein. It finally leads to mitochondrial biogenesis, metabolic reprogramming, and tumor cell differentiation [104]. 3Сlorgyline alone or with TMZ acts as monoamine oxidase A inhibitor and reduces tumor growth [125].…”

Section: Mitochondria Are the Central Hub Of The "Intrinsic" Apoptotimentioning

confidence: 99%

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Vasilev

Sofi

et al. 2018

Neuroglia

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Glioblastoma multiforme (GBM) is an extremely malignant type of brain cancer which originates from astrocytes or their precursors. Glioblastoma multiforme cells share some features with astrocytes but are characterized by highly unstable genomes with multiple driver mutations and aberrations. Effective therapies for GBM are lacking and hardly any progress has been made in the last 15 years in terms of improving the outcomes for patients. The lack of new especially targeted anti-GBM medications has prompted scientists in academia around the world to test whether any of the currently approved drugs might be used to fight this devastating disease. This approach is known as repurposing. Dozens of drugs have been reported to have anti-GBM properties in vitro but there is no solid evidence for the clinical efficacy of any of them. Perhaps the most interesting group of those repurposed are tricyclic antidepressants but the mechanism of their action on GBM cells remains obscure. In this brief review we consider various approaches to repurpose drugs for therapy of GBM and highlight their limitations. We also pay special attention to the mitochondria, which appear to be intimately involved in the process of apoptosis and could be a focus of future developments in search of a better treatment for patients suffering from GBM.

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The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes

Cited by 88 publications

References 45 publications

Negative regulation of miR‐1275 by H3K27me3 is critical for glial induction of glioblastoma cells

Negative regulation of miR‐1275 by H3K27me3 is critical for glial induction of glioblastoma cells

Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

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