Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Xue, Linyuan; Qi, Hongyu; Zhang, He; Ding, Liang; Huang, Qingxia; Zhao, Deyu; Wu, Bainan; Li, Xiangyan

doi:10.3389/fonc.2020.01510

Cited by 104 publications

(80 citation statements)

References 232 publications

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“…Consistent with this, ESCRT-I depletion led to elevated expression of genes encoding enzymes of cholesterol biosynthesis (Fig. 4A), suggestive of impaired delivery of cholesterol from lysosomes to the ER (Luo et al, 2020;Xue et al, 2020). In accordance with this, we observed that ESCRT-I depletion in RKO cells led to the accumulation of cholesterol (stained by filipin) in enlarged LAMP1-positive structures (Fig.…”

Section: Depletion Of Escrt-i Inhibits Lysosomal Cholesterol Efflux That Does Not Contribute To Activation Of Tfeb/tfe3 Signalingsupporting

confidence: 84%

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling

Wróbel

Szymańska

Budick-Harmelin

et al. 2021

Preprint

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Within the endolysosomal pathway in mammalian cells, ESCRT complexes facilitate degradation of proteins residing in endosomal membranes. Recent studies revealed that yeast ESCRT machinery also sorts ubiquitinated proteins from the vacuolar membrane for degradation in the vacuole lumen. However, whether mammalian ESCRTs perform a similar function at lysosomes remained unknown. Here, we show that ESCRT-I restricts the size of lysosomes and promotes degradation of proteins from lysosomal membranes, including MCOLN1, a Ca2+ channel protein. Upon ESCRT-I depletion, the lysosomal accumulation of non-degraded proteins coincided with elevated expression of genes annotated to cholesterol biosynthesis and biogenesis of lysosomes, indicative of response to lysosomal stress. Accordingly, the lack of ESCRT-I promoted abnormal cholesterol accumulation in lysosomes and activated TFEB/TFE3 transcription factors. Finally, we discovered that in contrast to basal TFEB/TFE3 signaling that depended on the availability of exogenous lipids, the stress-induced activation of this pathway was Ca2+-MCOLN1-dependent. Hence, we provide evidence that ESCRT-I is crucial for maintaining lysosomal homeostasis and we elucidate mechanisms distinguishing basal from lysosomal stress-induced TFEB/TFE3 signaling.

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Section: Depletion Of Escrt-i Inhibits Lysosomal Cholesterol Efflux That Does Not Contribute To Activation Of Tfeb/tfe3 Signalingsupporting

confidence: 84%

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling

Wróbel

Szymańska

Budick-Harmelin

et al. 2021

Preprint

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“…Consistently, advanced breast cancers upregulate CYP27A1 while decreasing the expression of CYP7B1, thereby promoting 27HC accumulation (31,270). Higher levels of intracellular cholesterol in cancer cells are determined by aberrant HMGCR activity, due to disrupted sterol-controlled feedback regulation or SREBP-mediated overexpression (271)(272)(273). In hypoxic tumor microenvironments, SREBPs and their downstream genes are strongly upregulated and support cell survival and tumor growth (274).…”

Section: Oncogenic Signaling and Cholesterol Homeostasismentioning

confidence: 98%

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

et al. 2021

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Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

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“…Because of their rapid proliferation, cancer cells require high levels of cholesterol, and increased cholesterol biosynthesis is a hallmark of many cancers ( Figure 2 ). SREBP2 and its target genes are markedly upregulated in prostate cancer, breast cancer, and HCC [ 61 ]. Cholesterol biosynthesis also plays an important role in the maintenance of cancer stem cells by activating sonic hedgehog and Notch pathway [ 62 ].…”

Section: Cell-intrinsic Effects Of Lipid Metabolic Reprogramming Imentioning

confidence: 99%

Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat

Matsushita

Nakagawa

Koike

2021

Cancers

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Lipids in our body, which are mainly composed of fatty acids, triacylglycerides, sphingolipids, phospholipids, and cholesterol, play important roles at the cellular level. In addition to being energy sources and structural components of biological membranes, several types of lipids serve as signaling molecules or secondary messengers. Metabolic reprogramming has been recognized as a hallmark of cancer, but changes in lipid metabolism in cancer have received less attention compared to glucose or glutamine metabolism. However, recent innovations in mass spectrometry- and chromatography-based lipidomics technologies have increased our understanding of the role of lipids in cancer. Changes in lipid metabolism, so-called “lipid metabolic reprogramming”, can affect cellular functions including the cell cycle, proliferation, growth, and differentiation, leading to carcinogenesis. Moreover, interactions between cancer cells and adjacent immune cells through altered lipid metabolism are known to support tumor growth and progression. Characterization of cancer-specific lipid metabolism can be used to identify novel metabolic targets for cancer treatment, and indeed, several clinical trials are currently underway. Thus, we discuss the latest findings on the roles of lipid metabolism in cancer biology and introduce current advances in lipidomics technologies, focusing on their applications in cancer research.

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Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Cited by 104 publications

References 232 publications

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling

ESCRT-I controls lysosomal membrane protein homeostasis and restricts MCOLN1-dependent TFEB/TFE3 signaling

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat

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