FATOSTATIN

  • Fatostatin blocks adipogenesis by inhibiting the activation of SREBPs (Sterol Regulatory Binding Proteins) LINKED with obesity, tumor growth, elevated PSA in males.

  • Fatostatin prevents increases in body weight, blood glucose and hepatic fat accumulation in obese mice.

Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):115-125. doi: 10.1016/j.bbadis.2018.10.026. Epub 2018 Oct 28.

SREBP-2 aggravates breast cancer associated osteolysis by promoting osteoclastogenesis and breast cancer metastasis.

Jie Z1, Xie Z1, Xu W1, Zhao X1, Jin G2, Sun X1, Huang B1, Tang P3, Wang G1, Shen S1, Qin A4, Fan S5.

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Abstract

Bone is one of the most common sites of breast cancer metastasis and a major cause of high mortality in these patients. Thus, further understanding the molecular mechanisms regulating breast cancer-induced osteolysis is critical for the development of more effective treatments. In this study, we demonstrated that important roles sterol regulatory element-binding protein 2 (SREBP-2) play in osteoclast formation a function, and in breast cancer metastasis.

SREBP-2 expression was found to be induced during the early stages of osteoclast formation under the control of the RANKL/cAMP-response element binding protein (CREB) signaling cascade. SREBP-2 is subsequently translocated into the nucleus where it participates with other transcriptional factors to induce the expression of NFATc1 required for mature osteoclast formation. Additionally, SREBP-2 was also found to be highly expressed in breast cancer tissues and correlated with a poor prognosis. SREBP-2 was similarly under the transcriptional control of CREB and its induction regulates the expression of matrix metalloproteinases (MMPs), key degradative enzymes involved in bone metastases by breast cancer cells. Accordingly, targeting of SREBP-2 with Fatostatin which specifically inhibits SCAP (SREBP cleavage-activating protein) and prevents SREBP activation, attenuated breast cancer-induced osteolysis in vivo. Collectively, our results suggest that SREBP-2 plays a critical role in regulating osteoclastogenesis and contributes to breast cancer-induced osteolysis. Thus, SREBP-2 inhibition is a potential therapeutic approach for breast cancer patients with osteolytic bone lesions.

Oncogenesis. 2018 Aug 24;7(8):66. doi: 10.1038/s41389-018-0076-0.

Fatostatin induces pro- and anti-apoptotic lipid accumulation in breast cancer.

Brovkovych V1, Izhar Y1, Danes JM1, Dubrovskyi O1, Sakallioglu IT2, Morrow LM2, Atilla-Gokcumen GE3, Frasor J4.

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Abstract

Given the dependence of cancers on de novo lipogenesis, we tested the effect of fatostatin, a small molecule thought to target this pathway by blocking activation of SREBP transcription factors, in breast cancer cell lines and xenograft tumors. We found that estrogen receptor (ER) positive cells were more sensitive to fatostatin than ER negative cells and responded with cell cycle arrest and apoptosis. Surprisingly, we found that rather than inhibiting lipogenesis, fatostatin caused an accumulation of lipids as a response to endoplasmic reticulum stress rather than inhibition of SREBP activity. In particular, ceramide and dihydroceramide levels increased and contributed to the apoptotic effects of fatostatin. In addition, an accumulation of triacylglycerides (TAGs), particularly those containing polyunsaturated fatty acids (PUFAs), was also observed as a result of elevated diacylglycerol transferase activity. Blocking PUFA-TAG production enhanced the apoptotic effect of fatostatin, suggesting that these lipids play a protective role and limit fatostatin response. Together, these findings indicate that the ability of breast cancer cells to respond to fatostatin depends on induction of endoplasmic reticulum stress and subsequent ceramide accumulation, and that limiting production of PUFA-TAGs may be therapeutically beneficial in specific tumor subtypes.

J Biol Chem. 2016 Jul 4. pii: jbc.C116.737346

Fatostatin inhibits cancer cell proliferation by affecting mitotic microtubule spindle assembly and cell division.

Gholkar AA1, Cheung K1, Williams KJ1, Lo YC1, Hamideh SA1, Nnebe C1, Khuu C1, Bensinger SJ1, Torres JZ2.

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Abstract

The sterol regulatory element binding protein (SREBP) transcription factors have become attractive targets for pharmacological inhibition in the treatment of metabolic diseases and cancer. SREBPs are critical for the production and metabolism of lipids and cholesterol, which are essential for cellular homeostasis and cell proliferation. Fatostatin was recently discovered as a specific inhibitor of SCAP (SREBP cleavage-activating protein), which is required for SREBP activation. Fatostatin possesses antitumor properties including the inhibition of cancer cell proliferation, invasion and migration, and it arrests cancer cells in G2/M phase. Although Fatostatin has been viewed as an antitumor agent due to its inhibition of SREBP and its effect on lipid metabolism, we show that Fatostatin's anticancer properties can also be attributed to its inhibition of cell division. We analyzed the effect of SREBP activity inhibitors including Fatostatin, PF-429242 and Betulin on the cell cycle and determined that only Fatostatin possessed antimitotic properties. Fatostatin inhibited Tubulin polymerization, arrested cells in mitosis, activated the spindle assembly checkpoint and triggered mitotic catastrophe and reduced cell viability. Thus Fatostatin's ability to inhibit SREBP activity and cell division could prove beneficial in treating aggressive types of cancers like glioblastomas that have elevated lipid metabolism, fast proliferation rates and often develop resistance to current anticancer therapies.

Oncotarget. 2015 Dec 1;6(38):41018-32. doi: 10.18632/oncotarget.5879.

Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations.

Li X1, Wu JB1, Chung LW1, Huang WC1.

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Abstract

Mutant p53 proteins (mutant p53s) have oncogenic gain-of-function properties correlated with tumor grade, castration resistance, and prostate cancer (PCa) tumor recurrence. Docetaxel is a standard first-line treatment for metastatic castration-resistant PCa (mCRPC) after the failure of hormone therapy. However, most mCRPC patients who receive docetaxel experience only transient benefits and rapidly develop incurable drug resistance, which is closely correlated with the p53 mutation status. Mutant p53s were recently reported to regulate the metabolic pathways via sterol regulatory element-binding proteins (SREBPs). Therefore, targeting the SREBP metabolic pathways with docetaxel as a combination therapy may offer a potential strategy to improve anti-tumor efficacy and delay cellular drug resistance in mCRPC harboring mutant p53s. Our previous data showed that fatostatin, a new SREBP inhibitor, inhibited cell proliferation and induced apoptosis in androgen receptor (AR)-positive PCa cell lines and xenograft mouse models. In this study, we demonstrated that mutant p53s activate the SREBP-mediated metabolic pathways in metastatic AR-negative PCa cells carrying mutant p53s. By blocking the SREBP pathways, fatostatin inhibited cell growth and induced apoptosis in metastatic AR-negative PCa cells harboring mutant p53s.

Furthermore, the combination of fatostatin and docetaxel resulted in greater proliferation inhibition and apoptosis induction compared with single agent treatment in PCa cells in vitro and in vivo, especially those with mutant p53s. These data suggest for the first time that fatostatin alone or in combination with docetaxel could be exploited as a novel and promising therapy for metastatic PCa harboring p53 mutations.

Oncotarget. 2015 Sep 8;6(26):22836-56.

Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation.

Schlaepfer IR1, Nambiar DK2,3, Ramteke A2,4, Kumar R2, Dhar D2, Agarwal C2,5, Bergman B6, Graner M7, Maroni P8, Singh RP3, Agarwal R2,5, Deep G2,5.

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Abstract

Hypoxia is an independent prognostic indicator of poor outcome in several malignancies. However, precise mechanism through which hypoxia promotes disease aggressiveness is still unclear. Here, we report that under hypoxia (1% O2), human prostate cancer (PCA) cells, and extracellular vesicles (EVs) released by these cells, are significantly enriched in triglycerides due to the activation of lipogenesis-related enzymes and signaling molecules. This is likely a survival response to hypoxic stress as accumulated lipids could support growth following reoxygenation. Consistent with this, significantly higher proliferation was observed in hypoxic PCA cells following reoxygenation associated with rapid use of accumulated lipids. Importantly, lipid utilization inhibition by CPT1 inhibitor etomoxir and shRNA-mediated CPT1-knockdown significantly compromised hypoxic PCA cell proliferation following reoxygenation. Furthermore, COX2 inhibitor celecoxib strongly reduced growth and invasiveness following hypoxic PCA cells reoxygenation, and inhibited invasiveness induced by hypoxic PCA EVs. This establishes a role for COX2 enzymatic products in the enhanced PCA growth and invasiveness. Importantly, concentration and loading of EVs secreted by PCA cells were significantly compromised under delipidized serum condition and by lipogenesis inhibitors (fatostatin and silibinin). Overall, present study highlights the biological significance of lipid accumulation in hypoxic PCA cells and its therapeutic relevance in PCA.

Oncotarget. 2014 Sep 16. [Epub ahead of print]

Silibinin inhibits aberrant lipid metabolism, proliferation and emergence of androgen-independence in prostate cancer cells via primarily targeting the sterol response element binding protein 1

Nambiar DK1, Deep G2, Singh RP3, Agarwal C2, Agarwal R2.

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  • 1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. School of Life Sciences, Jawaharlal Nehru University, India.

  • 2Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. University of Colorado Cancer Center, Aurora, CO, USA.

  • 3School of Life Sciences, Jawaharlal Nehru University, India.

Abstract

Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis.

 

Mol Cancer Ther. 2014 Apr;13(4):855-66. doi: 10.1158/1535-7163.MCT-13-0797. Epub 2014 Feb 3.

Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling

Li X1, Chen YT, Hu P, Huang WC.

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  • 1Authors' Affiliations: Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California and Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.

Abstract

Current research links aberrant lipogenesis and cholesterogenesis with prostate cancer development and progression. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis and cholesterogenesis via the regulation of genes related to fatty acid and cholesterol biosynthesis. Overexpression of SREBPs has been reported to be significantly associated with aggressive pathologic features in human prostate cancer. Our previous results showed that SREBP-1 promoted prostate cancer growth and castration resistance through induction of lipogenesis and androgen receptor (AR) activity. In the present study, we evaluated the anti-prostate tumor activity of a novel SREBP inhibitor, fatostatin. We found that fatostatin suppressed cell proliferation and anchorage-independent colony formation in both androgen-responsive LNCaP and androgen-insensitive C4-2B prostate cancer cells. Fatostatin also reduced in vitro invasion and migration in both the cell lines. Further, fatostatin caused G2-M cell-cycle arrest and induced apoptosis by increasing caspase-3/7 activity and the cleavages of caspase-3 and PARP.

The in vivo animal results demonstrated that fatostatin significantly inhibited subcutaneous C4-2B tumor growth and markedly decreased serum prostate-specific antigen (PSA) level compared with the control group. The in vitro and in vivo effects of fatostatin treatment were due to blockade of SREBP-regulated metabolic pathways and the AR signaling network. Our findings identify SREBP inhibition as a potential new therapeutic approach for the treatment of prostate cancer.

 

Am J Physiol Renal Physiol. 2012 Feb 1;302(3):F329-41. doi: 10.1152/ajprenal.00136.2011. Epub 2011 Oct 26.

SREBP-1 activation by glucose mediates TGF-β upregulation in mesangial cells

Uttarwar L1, Gao B, Ingram AJ, Krepinsky JC.

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  • 1St. Joseph's Hospital, Hamilton, ON, Canada.

Abstract

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. Recent studies showed that overexpression of the transcription factor sterol-responsive element-binding protein (SREBP)-1 induces pathology reminiscent of diabetic nephropathy, and SREBP-1 upregulation was observed in diabetic kidneys. We thus studied whether SREBP-1 is activated by high glucose (HG) and mediates its profibrogenic responses. In primary rat mesangial cells, HG activated SREBP-1 by 30 min, seen by the appearance of its cleaved nuclear form (nSREBP-1), EMSA, and by activation of an SREBP-1 response element (SRE)-driven green fluorescent protein construct. Activation was dose dependent and not induced by an osmotic control. Site 1 protease was required, since its inhibition by AEBSF prevented SREBP-1 activation. SCAP, the ER-associated chaperone for SREBP-1, was also necessary since its inhibitor fatostatin also blocked SREBP-1 activation. Signaling through the EGFR/phosphatidylinositol 3-kinase (PI3K) pathway, which we previously showed mediates HG-induced TGF-β1 upregulation, and through RhoA, were upstream of SREBP-1 activation (Wu D, Peng F, Zhang B, Ingram AJ, Gao B, Krepinsky JC. Diabetologia 50: 2008-2018, 2007; Wu D, Peng F, Zhang B, Ingram AJ, Kelly DJ, Gilbert RE, Gao B, Krepinsky JC. J Am Soc Nephrol 20: 554-566, 2009). Fatostatin and AEBSF prevented HG-induced TGF-β1 upregulation by Northern blot analysis, and HG-induced TGF-β1 promoter activation was inhibited by both fatostatin and dominant negative SREBP-1a. Chromatin immunoprecipitation analysis confirmed that HG led to SREBP-1 binding to the TGF-β1 promoter in a region containing a putative SREBP-1 binding site (SRE). Thus HG-induced SREBP-1 activation requires EGFR/PI3K/RhoA signaling and SCAP-mediated transport to the Golgi for its proteolytic cleavage. Activated SREBP-1 binds to the TGF-β promoter, resulting in TGF-β1 upregulation in response to HG. SREBP-1 thus provides a potential novel therapeutic target for the treatment of diabetic nephropathy.

 

J Med Chem. 2011 Jul 14;54(13):4923-7. doi: 10.1021/jm200304y. Epub 2011 Jun 8.

Synthesis and evaluation of diarylthiazole derivatives that inhibit activation of sterol regulatory element-binding proteins

Kamisuki S1, Shirakawa T, Kugimiya A, Abu-Elheiga L, Choo HY, Yamada K, Shimogawa H, Wakil SJ, Uesugi M.

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  • 1Institute for Chemical Research, Kyoto University, Uji, Kyoto, Japan.

Abstract

Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure-activity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development.

 

Chem Biol. 2009 Aug 28;16(8):882-92. doi: 10.1016/j.chembiol.2009.07.007.

A small molecule that blocks fat synthesis by inhibiting the activation of SREBP

Kamisuki S1, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y, Shinohara T, Kawazoe Y, Sato S, Asakura K, Choo HY, Sakai J, Wakil SJ, Uesugi M.

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  • 1Institute for Chemical Research, Kyoto University, Uji, Japan.

Abstract

Sterol regulatory element binding proteins (SREBPs) are transcription factors that activate transcription of the genes involved in cholesterol and fatty acid biosynthesis. In the present study, we show that a small synthetic molecule we previously discovered to block adipogenesis is an inhibitor of the SREBP activation.

The diarylthiazole derivative, now called fatostatin, impairs the activation process of SREBPs, thereby decreasing the transcription of lipogenic genes in cells. Our analysis suggests that fatostatin inhibits the ER-Golgi translocation of SREBPs through binding to their escort protein, the SREBP cleavage-activating protein (SCAP), at a distinct site from the sterol-binding domain. Fatostatin blocked increases in body weight, blood glucose, and hepatic fat accumulation in obese ob/ob mice, even under uncontrolled food intake. Fatostatin may serve as a tool for gaining further insights into the regulation of SREBP.

 

Chem Biol. 2009 Aug 28;16(8):798-800. doi: 10.1016/j.chembiol.2009.08.003.

Putative fat fighter hits the middle man

Krycer JR1, Brown AJ.

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  • 1University of New South Wales, Sydney, Australia.

Abstract

In this issue, Kamisuki and colleagues characterize fatostatin. This compound inhibits the activity of SREBPs, the master transcription factors of lipid homeostasis. This useful laboratory tool also improved the lipid profile of obese mice; does this have clinical implications?

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