Lipid metabolism emerges as a promising target for malignant glioma therapy

Guo, Deliang; Bell, Erica H.; Chakravarti, Arnab

doi:10.2217/cns.13.20

Cited by 157 publications

(160 citation statements)

References 95 publications

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“…Accumulating evidence has shown that SCAP/SREBPs play important roles in malignancies, connecting oncogenic signaling to lipid metabolism alterations, leading to rapid tumor growth (Figure 1) [13, 60, 61, 76–78, 80, 82]. Multiple studies have suggested that SCAP/SREBPs are very promising molecular targets in cancer treatment.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous studies demonstrated that SREBP-1 is highly upregulated by oncogenic EGFR signaling in GBM [13, 60, 61, 76–81]. We found that GBM tumors bearing amplified EGFR, or expressing EGFRvIII, the constitutively active form of the receptor that lacks a portion of the extracellular ligand-binding domain, were greatly dependent on SREBP-1-mediated lipid synthesis and uptake for rapid growth [61].…”

Section: Activation Of Scap/srebps In Cancermentioning

confidence: 99%

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SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Cheng

Guo

2018

CTMC

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Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavage-activating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Activation Of Scap/srebps In Cancermentioning

confidence: 99%

SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

Cheng

Guo

2018

CTMC

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“…Previous work from our group has found that the size of lipid droplets can vary across several neural-derived tumour cell lines and that both size and composition can change in response to treatments that target metabolic pathways [26,27]. Disruption of lipid metabolism in glioma has also been identified as a potential therapeutic target [7,28]. As lipid accumulation appears to be an important indicator of increased metabolic state within high grade malignancies there is likely to be biological and diagnostic value to observing lipid droplets in biopsied brain tumours.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of lipid droplets in cancer metabolism is gaining clinical significance with many tumours including glioma found to have altered lipid profiles that change with grade and in response to treatment [3,6,7]. Lipid accumulation has been detected in high grade gliomas using ex-vivo nuclear magnetic resonance (NMR) techniques and evidence from electron microscopy and fluorescent labelling with Nile Red has determined that cytoplasmic lipid droplets are the major contributor to this lipid [8,9].…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical staining of lipid droplets with adipophilin in paraffin-embedded glioma tissue identifies an association between lipid droplets and tumour grade

Kohe¹,

Colmenero²,

McConville³

et al. 2017

J Histol Histopathol

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Background: Cytoplasmic lipid droplets are important in cancer metabolism and a clear relationship has been established between their accumulation and increased tumour grade in glioma. The development of the novel immunohistochemical marker adipophilin has proven to be a useful method of detecting lipid droplets in paraffin embedded tissue from many diseases. Our aim was to assess the distribution of adipophilin stained lipid droplets in paraffin embedded glioma tissue and to evaluate whether it is a useful indicator of lipid droplets in brain tumours. Methods: Immunohistochemical staining for adipophilin was undertaken in a tissue microarray containing 65 paraffin embedded gliomas of varying grade. The number of tumour cells containing adipophilin positive lipid droplets was then quantified and statistically analysed. Results: We found a statistically significant accumulation of lipid droplets in high grade glioblastoma compared to low grade astrocytomas when we quantified the percentage of tumour cells containing adipophilin-positive lipid droplets (p<0.001). A significant positive correlation (rs=0.83) was detected between increasing tumour grade and the percentage of tumour cells containing lipid droplets, p=0.0001. Conclusions:We have determined that adipophilin is a useful immunohistochemical marker of lipid droplets in brain tumours. The ability to detect lipid droplets within paraffin embedded gliomas will greatly facilitate the evaluation of this tumour characteristic which is related to grade and prognosis.

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“…2–4 We found that oncogenic epidermal growth factor receptor (EGFR) signaling upregulates sterol regulatory element-binding protein-1 (SREBP-1), a membrane bound transcription factor with a central role in lipid metabolism. 5–7 These studies demonstrated that oncogenic signaling hijacks the intrinsic machinery of lipid metabolism, enhancing lipid synthesis and uptake to promote tumor growth.…”

mentioning

confidence: 99%