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

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

Authors:
- Shuhong Gao
- Zhengzheng Shi
- Xin Li
- Wenzhi Li
- Yiling Wang
- Zhiming Liu
- Jie Jiang
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Affiliations: Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China, Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Gynecology, Zaozhuang Municipal Hospital, Zaozhuang, Shandong 277000, P.R. China
Published online on: February 13, 2018 https://doi.org/10.3892/or.2018.6265
Pages: 1919-1929

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Abstract

Fatostatin, a chemical inhibitor of the sterol regulatory element‑binding protein (SREBP) pathway, has been reported to possess high antitumor activity against prostate and pancreatic cancer. The main aim of the present study was to investigate the effects and mechanism of fatostatin in endometrial carcinoma (EC). In the present study, we determined that fatostatin inhibited EC cell viability and colony formation capacity, decreased the invasive and migratory capacities of EC cells, induced EC cell cycle arrest at the G2/M phase and stimulated caspase‑mediated apoptosis of EC cells. In addition, fatostatin significantly decreased the protein expression levels of nuclear SREBPs and their downstream genes and increased the protein expression levels of cleaved caspase‑9, caspase‑3 and PARP in EC cells. In addition, the mRNA expression levels of SREBP‑controlled downstream genes were also significantly downregulated. The quantification assays of fatty acids and total cholesterol revealed that the levels of free fatty acids and total cholesterol in EC cells were decreased. The present study indicated that fatostatin exhibited antitumor effects by blocking SREBP‑regulated metabolic pathways and inducing caspase‑mediated apoptosis in EC and may be a potent therapeutic strategy for the treatment of EC.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
2	Suri V and Arora A: Management of endometrial cancer: A review. Rev Recent Clin Trials. 10:309–316. 2015. View Article : Google Scholar : PubMed/NCBI
3	Gunderson CC, Fader AN, Carson KA and Bristow RE: Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: A systematic review. Gynecol Oncol. 125:477–482. 2012. View Article : Google Scholar : PubMed/NCBI
4	Hahn HS, Yoon SG, Hong JS, Hong SR, Park SJ, Lim JY, Kwon YS, Lee IH, Lim KT, Lee KH, et al: Conservative treatment with progestin and pregnancy outcomes in endometrial cancer. Int J Gynecol Cancer. 19:1068–1073. 2009. View Article : Google Scholar : PubMed/NCBI
5	Horton JD, Goldstein JL and Brown MS: SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 109:1125–1131. 2002. View Article : Google Scholar : PubMed/NCBI
6	Li JN, Mahmoud MA, Han WF, Ripple M and Pizer ES: Sterol regulatory element-binding protein-1 participates in the regulation of fatty acid synthase expression in colorectal neoplasia. Exp Cell Res. 261:159–165. 2000. View Article : Google Scholar : PubMed/NCBI
7	Swinnen JV: Increased lipogenesis in steroid-responsive cancer cells: Mechanisms of regulation, role in cancer cell biology and perspectives on clinical applications. Verh K Acad Geneeskd Belg. 63:321–333. 2001.PubMed/NCBI
8	Yang Yu, Morin PJ, Han WF, Chen T, Bornman DM, Gabrielson EW and Pizer ES: Regulation of fatty acid synthase expression in breast cancer by sterol regulatory element binding protein-1c. Exp Cell Res. 282:132–137. 2003. View Article : Google Scholar : PubMed/NCBI
9	Yahagi N, Shimano H, Hasegawa K, Ohashi K, Matsuzaka T, Najima Y, Sekiya M, Tomita S, Okazaki H, Tamura Y, et al: Co-ordinate activation of lipogenic enzymes in hepatocellular carcinoma. Eur J Cancer. 41:1316–1322. 2005. View Article : Google Scholar : PubMed/NCBI
10	Li W, Tai Y, Zhou J, Gu W, Bai Z, Zhou T, Zhong Z, McCue PA, Sang N, Ji JY, et al: Repression of endometrial tumor growth by targeting SREBP1 and lipogenesis. Cell Cycle. 11:2348–2358. 2012. View Article : Google Scholar : PubMed/NCBI
11	Eberhard Y, Gronda M, Hurren R, Datti A, Maclean N, Ketela T, Moffat J, Wraba JL and Schimmer AD: Inhibition of SREBP1 sensitizes cells to death ligands. Oncotarget. 2:186–196. 2011. View Article : Google Scholar : PubMed/NCBI
12	Kamisuki S, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y, Shinohara T, Kawazoe Y, Sato S, Asakura K, et al: A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol. 16:882–892. 2009. View Article : Google Scholar : PubMed/NCBI
13	Shao W, Machamer CE and Espenshade PJ: Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res. 57:1564–73. 2016. View Article : Google Scholar : PubMed/NCBI
14	Li X, Chen YT, Hu P and Huang WC: Fatostatin displays high anti-tumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol Cancer Ther. 13:855–866. 2014. View Article : Google Scholar : PubMed/NCBI
15	Li X, Wu JB, Chung LW and Huang WC: Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations. Oncotarget. 6:41018–41032. 2015. View Article : Google Scholar : PubMed/NCBI
16	Siqingaowa, Sekar S, Gopalakrishnan V and Taghibiglou C: Sterol regulatory element-binding protein 1 inhibitors decrease pancreatic cancer cell viability and proliferation. Biochem Biophys Res Commun. 488:136–140. 2017. View Article : Google Scholar : PubMed/NCBI
17	Tennant DA, Durán RV and Gottlieb E: Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 10:267–277. 2010. View Article : Google Scholar : PubMed/NCBI
18	Ward PS and Thompson CB: Metabolic reprogramming: A cancer hallmark even warburg did not anticipate. Cancer Cell. 21:297–308. 2012. View Article : Google Scholar : PubMed/NCBI
19	Deberardinis RJ, Sayed N, Ditsworth D and Thompson CB: Brick by brick: Metabolism and tumor cell growth. Curr Opin Genet Dev. 18:54–61. 2008. View Article : Google Scholar : PubMed/NCBI
20	Byrne FL, Poon IK, Modesitt SC, Tomsig JL, Chow JD, Healy ME, Baker WD, Atkins KA, Lancaster JM, Marchion DC, et al: Metabolic vulnerabilities in endometrial cancer. Cancer Res. 74:5832–5845. 2014. View Article : Google Scholar : PubMed/NCBI
21	Williams KJ, Argus JP, Zhu Y, Wilks MQ, Marbois BN, York AG, Kidani Y, Pourzia AL, Akhavan D, Lisiero DN, et al: An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 73:2850–2862. 2013. View Article : Google Scholar : PubMed/NCBI
22	Radhakrishnan A, Goldstein JL, McDonald JG and Brown MS: Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: A delicate balance. Cell Metab. 8:512–521. 2008. View Article : Google Scholar : PubMed/NCBI
23	Goldstein JL, DeBose-Boyd RA and Brown MS: Protein sensors for membrane sterols. Cell. 124:35–46. 2006. View Article : Google Scholar : PubMed/NCBI
24	Gholkar AA, Cheung K, Williams KJ, Lo YC, Hamideh SA, Nnebe C, Khuu C, Bensinger SJ and Torres JZ: Fatostatin inhibits cancer cell proliferation by affecting mitotic microtubule spindle assembly and cell division. J Biol Chem. 291:17001–17008. 2016. View Article : Google Scholar : PubMed/NCBI
25	Johannes VS, Koen B and Guido V: Increased lipogenesis in cancer cells: New players, novel targets. Curr Opin Clin Nutr Metab Care. 9:358–365. 2006. View Article : Google Scholar : PubMed/NCBI
26	Menendez JA and Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 7:763–777. 2007. View Article : Google Scholar : PubMed/NCBI
27	Qiu C, Dongol S, Lv QT, Gao X and Jiang J: Sterol regulatory element-binding protein-1/fatty acid synthase involvement in proliferation inhibition and apoptosis promotion induced by progesterone in endometrial cancer. Int J Gynecol Cancer. 23:1629–1634. 2013. View Article : Google Scholar : PubMed/NCBI
28	Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA and Thompson CB: ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 8:311–321. 2005. View Article : Google Scholar : PubMed/NCBI
29	Igal RA: Stearoyl-CoA desaturase-1: A novel key player in the mechanisms of cell proliferation, programmed cell death and transformation to cancer. Carcinogenesis. 31:1509–1515. 2010. View Article : Google Scholar : PubMed/NCBI
30	Guo D, Bell EH and Chakravarti A: Lipid metabolism emerges as a promising target for malignant glioma therapy. CNS Oncol. 2:289–299. 2013. View Article : Google Scholar : PubMed/NCBI
31	Freeman MR, Cinar B, Kim J, Mukhopadhyay NK, Di Vizio D, Adam RM and Solomon KR: Transit of hormonal and EGF receptor-dependent signals through cholesterol-rich membranes. Steroids. 72:210–217. 2007. View Article : Google Scholar : PubMed/NCBI
32	Lingwood D and Simons K: Lipid rafts as a membrane-organizing principle. Science. 327:46–50. 2010. View Article : Google Scholar : PubMed/NCBI
33	Pandyra AA, Mullen PJ, Goard CA, Ericson E, Sharma P, Kalkat M, Yu R, Pong JT, Brown KR, Hart T, et al: Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death. Oncotarget. 6:26909–26921. 2015. View Article : Google Scholar : PubMed/NCBI
34	Wiemer AJ, Hohl RJ and Wiemer DF: The intermediate enzymes of isoprenoid metabolism as anticancer targets. Anticancer Agents Med Chem. 9:526–542. 2009. View Article : Google Scholar : PubMed/NCBI
35	Nevadunsky NS, Van Arsdale A, Strickler HD, Spoozak LA, Moadel A, Kaur G, Girda E, Goldberg GL and Einstein MH: Association between statin use and endometrial cancer survival. Obstet Gynecol. 126:144–150. 2015. View Article : Google Scholar : PubMed/NCBI
36	Indran IR, Tufo G, Pervaiz S and Brenner C: Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Biophys Acta. 1807:735–745. 2011. View Article : Google Scholar : PubMed/NCBI
37	Vyas VK, Chintha C and Pandya MR: Biology and medicinal chemistry approaches towards various apoptosis inducers. Anticancer Agents Med Chem. 13:433–455. 2013. View Article : Google Scholar : PubMed/NCBI
38	Soldatenkov VA and Potaman VN: DNA-binding properties of poly(ADP-ribose) polymerase: A target for anticancer therapy. Curr Drug Targets. 5:357–365. 2004. View Article : Google Scholar : PubMed/NCBI