Fatostatin suppresses growth and enhances apoptosis by blocking SREBP-regulated metabolic pathways in endometrial carcinoma

Gao, Shuhong; Shi, Zhengzheng; Li, Xin; Li, Wenzhi; Wang, Yiling; Liu, Zhiming; Jiang, Jie

doi:10.3892/or.2018.6265

Cited by 18 publications

(19 citation statements)

References 34 publications

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“…In PCa, in vitro and in vivo studies reveal that fatostatin suppresses cell proliferation and induces apoptosis through blockade of SREBP-regulated metabolic pathways (133), similar to the findings in endometrial carcinoma (140). The combination of fatostatin with docetaxel significantly increases proliferation inhibition and apoptosis induction in metastatic PCa harboring p53 mutations, compared with fatostatin alone (142).…”

Section: Targeting the Srebp-2-regulated Mevalonate Pathway For Cancementioning

confidence: 74%

“…Fatostatin, a nonsterol diarylthazole derivative, was first reported to inhibit insulin-induced adipogenesis and reduce body weight by blocking nuclear translocation of SREBPs in obese mice (137,138). Fatostatin has been used for treating prostate (133), breast (139), and endometrial cancers (140). Mechanistically, fatostatin directly binds SCAP and blocks its transport from ER to Golgi apparatus, then inhibits the activation of SREBPs (138).…”

Section: Targeting the Srebp-2-regulated Mevalonate Pathway For Cancementioning

confidence: 99%

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Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

et al. 2020

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Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

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Section: Targeting the Srebp-2-regulated Mevalonate Pathway For Cancementioning

confidence: 74%

Section: Targeting the Srebp-2-regulated Mevalonate Pathway For Cancementioning

confidence: 99%

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

et al. 2020

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“…Results from preclinical studies showed that the AKT/mTORC1/SREBP pathway takes part in cancer cell growth by inducing biosynthesis of cholesterol (Porstmann et al, 2008). Finally, direct inhibition of SREBP2 (e.g., using fatostatin), resulting in a decrease in cholesterol content, may represent an interesting target in the treatment of a wide range of cancers (Gholkar et al, 2016;Gao et al, 2018).…”

Section: Srebpmentioning

confidence: 99%

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

Vona

Iessi

Matarrese

2021

Front. Cell Dev. Biol.

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Cholesterol is a lipid molecule that plays an essential role in a number of biological processes, both physiological and pathological. It is an essential structural constituent of cell membranes, and it is fundamental for biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the major lipid component of lipid rafts, a sort of lipid-based structures that regulate the assembly and functioning of numerous cell signaling pathways, including those related to cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every stage: import, synthesis, export, metabolism, and storage. The alterations of this homeostatic balance are known to be associated with cardiovascular diseases and atherosclerosis, but mounting evidence also connects these behaviors to increased cancer risks. Although there is conflicting evidence on the role of cholesterol in cancer development, most of the studies consistently suggest that a dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of major players in cholesterol regulation and the organization of lipid rafts, which could represent promising therapeutic targets.

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“…Gholkar and coworkers ( 284 ) investigated the mechanism underlying the antitumor effect of fatostatin in different types of tumors, such as human breast and cervix cells, showing its ability to block the tubulin polymerization and arrest cells in mitosis ( 284 ). Fatostatin reduced cell viability in endometrial cancer ( 151 , 152 ) and decreased the tumor growth in xenograft mice enhancing their survival rate ( 151 ). ER-positive breast cancer cells treated with fatostatin showed decreased cell viability and higher lipid accumulation.…”

Section: Cholesterol Metabolic Reprogramming In Cancer: Pharmacological Targetingmentioning

confidence: 99%

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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Fatostatin suppresses growth and enhances apoptosis by blocking SREBP-regulated metabolic pathways in endometrial carcinoma

Cited by 18 publications

References 34 publications

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

Role of Cholesterol and Lipid Rafts in Cancer Signaling: A Promising Therapeutic Opportunity?

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

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