Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression—An in vitro study

English version

Autoři: Vijayalakshmi N. Ayyagari ^aff001; Xinjia Wang ^aff001; Paula L. Diaz-Sylvester ^aff001; Kathleen Groesch ^aff001; Laurent Brard ^aff001
Působiště autorů: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Southern Illinois University School of Medicine, Springfield, IL, United States America ^aff001; Center for Clinical Research, Southern Illinois University School of Medicine, Springfield, IL, United States America ^aff002; Simmons Cancer Institute at Southern Illinois University School of Medicine, Springfield, IL, United States America ^aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0228024

Souhrn

Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT-1) mediated cholesterol ester has been shown to contribute to cancer progression in various cancers including leukemia, glioma, breast, pancreatic and prostate cancers. However, the significance of ACAT-1 and cholesterol esters (CE) is relatively understudied in ovarian cancer. In this in vitro study, we assessed the expression and contribution of ACAT-1 in ovarian cancer progression. We observed a significant increase in the expression of ACAT-1 and CE levels in a panel of ovarian cancer cell lines (OC-314, SKOV-3 and IGROV-1) compared to primary ovarian epithelial cells (normal controls). To confirm the tumor promoting capacity of ACAT-1, we inhibited ACAT-1 expression and activity by treating our cell lines with an ACAT inhibitor, avasimibe, or by stable transfection with ACAT-1 specific short hairpin RNA (shRNA). We observed significant suppression of cell proliferation, migration and invasion in ACAT-1 knockdown ovarian cancer cell lines compared to their respective controls (cell lines transfected with scrambled shRNA). ACAT-1 inhibition enhanced apoptosis with a concurrent increase in caspases 3/7 activity and decreased mitochondrial membrane potential. Increased generation of reactive oxygen species (ROS) coupled with increased expression of p53 may be the mechanism(s) underlying pro-apoptotic action of ACAT-1 inhibition. Additionally, ACAT-1 inhibited ovarian cancer cell lines displayed enhanced chemosensitivity to cisplatin treatment. These results suggest ACAT-1 may be a potential new target for the treatment of ovarian cancer.

Klíčová slova:

Apoptosis – Cell cycle and cell division – Cell cycle inhibitors – Cell proliferation – Cell staining – Cholesterol – Ovarian cancer – Reactive oxygen species

Zdroje

1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society. 2013. p. 18.

2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300. Epub 2010/07/09. doi: 10.3322/caac.20073 20610543.

3. Herzog TJ. The current treatment of recurrent ovarian cancer. Curr Oncol Rep. 2006;8(6):448–54. Epub 2006/10/17. doi: 10.1007/s11912-006-0074-9 17040623.

4. Agarwal R, Kaye SB. Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 2003;3(7):502–16. Epub 2003/07/02. doi: 10.1038/nrc1123 12835670.

5. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med. 1996;334(1):1–6. Epub 1996/01/04. doi: 10.1056/NEJM199601043340101 7494563.

6. Piccart MJ, Bertelsen K, James K, Cassidy J, Mangioni C, Simonsen E, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst. 2000;92(9):699–708. Epub 2000/05/04. doi: 10.1093/jnci/92.9.699 10793106.

7. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell metabolism. 2013;18(2):153–61. Epub 2013/06/25. doi: 10.1016/j.cmet.2013.05.017 23791484; PubMed Central PMCID: PMC3742569.

8. Luo X, Cheng C, Tan Z, Li N, Tang M, Yang L, et al. Emerging roles of lipid metabolism in cancer metastasis. Mol Cancer. 2017;16(1):76. Epub 2017/04/13. doi: 10.1186/s12943-017-0646-3 28399876; PubMed Central PMCID: PMC5387196.

9. Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis. 2016;5:e189. Epub 2016/01/26. doi: 10.1038/oncsis.2015.49 26807644; PubMed Central PMCID: PMC4728678.

10. Antalis CJ, Arnold T, Rasool T, Lee B, Buhman KK, Siddiqui RA. High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast Cancer Res Treat. 2010;122(3):661–70. Epub 2009/10/24. doi: 10.1007/s10549-009-0594-8 19851860.

11. Mulas MF, Abete C, Pulisci D, Pani A, Massidda B, Dessi S, et al. Cholesterol esters as growth regulators of lymphocytic leukaemia cells. Cell Prolif. 2011;44(4):360–71. Epub 2011/06/08. doi: 10.1111/j.1365-2184.2011.00758.x 21645151.

12. Bemlih S, Poirier MD, El Andaloussi A. Acyl-coenzyme A: cholesterol acyltransferase inhibitor Avasimibe affect survival and proliferation of glioma tumor cell lines. Cancer biology & therapy. 2010;9(12):1025–32. Epub 2010/04/21. doi: 10.4161/cbt.9.12.11875 20404512.

13. Geng F, Guo D. Lipid droplets, potential biomarker and metabolic target in glioblastoma. Intern Med Rev (Wash D C). 2017;3(5). Epub 2017/10/17. doi: 10.18103/imr.v3i5.443 29034362; PubMed Central PMCID: PMC5639724.

14. Yue S, Li J, Lee SY, Lee HJ, Shao T, Song B, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell metabolism. 2014;19(3):393–406. Epub 2014/03/13. doi: 10.1016/j.cmet.2014.01.019 24606897; PubMed Central PMCID: PMC3969850.

15. Accioly MT, Pacheco P, Maya-Monteiro CM, Carrossini N, Robbs BK, Oliveira SS, et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res. 2008;68(6):1732–40. Epub 2008/03/15. doi: 10.1158/0008-5472.CAN-07-1999 18339853.

16. Gaida MM, Mayer C, Dapunt U, Stegmaier S, Schirmacher P, Wabnitz GH, et al. Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule. Oncotarget. 2016;7(11):12623–32. Epub 2016/02/11. doi: 10.18632/oncotarget.7206 26862855; PubMed Central PMCID: PMC4914309.

17. Koizume S, Miyagi Y. Lipid Droplets: A Key Cellular Organelle Associated with Cancer Cell Survival under Normoxia and Hypoxia. Int J Mol Sci. 2016;17(9). Epub 2016/09/03. doi: 10.3390/ijms17091430 27589734; PubMed Central PMCID: PMC5037709.

18. Danilo C, Gutierrez-Pajares JL, Mainieri MA, Mercier I, Lisanti MP, Frank PG. Scavenger receptor class B type I regulates cellular cholesterol metabolism and cell signaling associated with breast cancer development. Breast Cancer Res. 2013;15(5):R87. Epub 2013/09/26. doi: 10.1186/bcr3483 24060386; PubMed Central PMCID: PMC3978612.

19. Paillasse MR, de Medina P, Amouroux G, Mhamdi L, Poirot M, Silvente-Poirot S. Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion. J Lipid Res. 2009;50(11):2203–11. Epub 2009/06/09. doi: 10.1194/jlr.M800668-JLR200 19502590; PubMed Central PMCID: PMC2759826.

20. Tosi MR, Tugnoli V. Cholesteryl esters in malignancy. Clin Chim Acta. 2005;359(1–2):27–45. Epub 2005/06/09. doi: 10.1016/j.cccn.2005.04.003 15939411.

21. Chang TY, Li BL, Chang CC, Urano Y. Acyl-coenzyme A:cholesterol acyltransferases. American journal of physiology Endocrinology and metabolism. 2009;297(1):E1–9. Epub 2009/01/15. doi: 10.1152/ajpendo.90926.2008 19141679; PubMed Central PMCID: PMC2711667.

22. Geng F, Cheng X, Wu X, Yoo JY, Cheng C, Guo JY, et al. Inhibition of SOAT1 Suppresses Glioblastoma Growth via Blocking SREBP-1-Mediated Lipogenesis. Clin Cancer Res. 2016;22(21):5337–48. Epub 2016/11/03. doi: 10.1158/1078-0432.CCR-15-2973 27281560; PubMed Central PMCID: PMC5093025.

23. Ohmoto T, Nishitsuji K, Yoshitani N, Mizuguchi M, Yanagisawa Y, Saito H, et al. K604, a specific acylCoA:cholesterol acyltransferase 1 inhibitor, suppresses proliferation of U251MG glioblastoma cells. Mol Med Rep. 2015;12(4):6037–42. Epub 2015/08/08. doi: 10.3892/mmr.2015.4200 26252415.

24. LaPensee CR, Mann JE, Rainey WE, Crudo V, Hunt SW 3rd, Hammer GD. ATR-101, a Selective and Potent Inhibitor of Acyl-CoA Acyltransferase 1, Induces Apoptosis in H295R Adrenocortical Cells and in the Adrenal Cortex of Dogs. Endocrinology. 2016;157(5):1775–88. Epub 2016/03/18. doi: 10.1210/en.2015-2052 26986192.

25. Stopsack KH, Gerke TA, Andren O, Andersson SO, Giovannucci EL, Mucci LA, et al. Cholesterol uptake and regulation in high-grade and lethal prostate cancers. Carcinogenesis. 2017;38(8):806–11. Epub 2017/06/09. doi: 10.1093/carcin/bgx058 28595267; PubMed Central PMCID: PMC6074871.

26. Saraon P, Trudel D, Kron K, Dmitromanolakis A, Trachtenberg J, Bapat B, et al. Evaluation and prognostic significance of ACAT1 as a marker of prostate cancer progression. Prostate. 2014;74(4):372–80. Epub 2013/12/07. doi: 10.1002/pros.22758 24311408.

27. Li J, Gu D, Lee SS, Song B, Bandyopadhyay S, Chen S, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene. 2016;35(50):6378–88. Epub 2016/05/03. doi: 10.1038/onc.2016.168 27132508; PubMed Central PMCID: PMC5093084.

28. Poirot M, Silvente-Poirot S, Weichselbaum RR. Cholesterol metabolism and resistance to tamoxifen. Curr Opin Pharmacol. 2012;12(6):683–9. Epub 2012/10/16. doi: 10.1016/j.coph.2012.09.007 23063783.

29. Li J, Qu X, Tian J, Zhang JT, Cheng JX. Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation. PLoS One. 2018;13(2):e0193318. Epub 2018/03/01. doi: 10.1371/journal.pone.0193318 29489864; PubMed Central PMCID: PMC5831104.

30. Ayyagari VN, Brard L. Bithionol inhibits ovarian cancer cell growth in vitro—studies on mechanism(s) of action. BMC Cancer. 2014;14:61. Epub 2014/02/06. doi: 10.1186/1471-2407-14-61 24495391; PubMed Central PMCID: PMC3922745.

31. Bradley EC, Catino JJ, Issell BF, Poiesz B, Hustad JM, Dalton T, et al. Cell-mediated inhibition of tumor colony formation in agarose by resting and interleukin 2-stimulated human lymphocytes. Cancer Res. 1985;45(4):1464–8. Epub 1985/04/01. 3872166.

32. Kasibhatla S, Amarante-Mendes GP, Finucane D, Brunner T, Bossy-Wetzel E, Green DR. Detection of phosphatidylserine externalization during apoptosis. CSH Protoc. 2006;2006(3). Epub 2006/01/01. 10.1101/pdb.prot4494. doi: 10.1101/pdb.prot4494 22485875.

33. Zamzami N, Marchetti P, Castedo M, Decaudin D, Macho A, Hirsch T, et al. Sequential reduction of mitochondrial transmembrane potential and generation of reactive oxygen species in early programmed cell death. J Exp Med. 1995;182(2):367–77. Epub 1995/08/01. doi: 10.1084/jem.182.2.367 7629499; PubMed Central PMCID: PMC2192111.

34. Pampalakis G, Politi AL, Papanastasiou A, Sotiropoulou G. Distinct cholesterogenic and lipidogenic gene expression patterns in ovarian cancer—a new pool of biomarkers. Genes Cancer. 2015;6(11–12):472–9. Epub 2016/01/26. doi: 10.18632/genesandcancer.87 26807200; PubMed Central PMCID: PMC4701226.

35. Lee SS, Li J, Tai JN, Ratliff TL, Park K, Cheng JX. Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment. ACS Nano. 2015;9(3):2420–32. Epub 2015/02/11. doi: 10.1021/nn504025a 25662106; PubMed Central PMCID: PMC5909415.

36. Bandyopadhyay S, Li J, Traer E, Tyner JW, Zhou A, Oh ST, et al. Cholesterol esterification inhibition and imatinib treatment synergistically inhibit growth of BCR-ABL mutation-independent resistant chronic myelogenous leukemia. PLoS One. 2017;12(7):e0179558. Epub 2017/07/19. doi: 10.1371/journal.pone.0179558 28719608; PubMed Central PMCID: PMC5515395.

37. Murai T. The role of lipid rafts in cancer cell adhesion and migration. Int J Cell Biol. 2012;2012:763283. Epub 2012/01/19. doi: 10.1155/2012/763283 22253629; PubMed Central PMCID: PMC3255102.

38. McDonnel AC, Van Kirk EA, Isaak DD, Murdoch WJ. Inhibitory effects of progesterone on plasma membrane fluidity and tumorigenic potential of ovarian epithelial cancer cells. Exp Biol Med (Maywood). 2003;228(3):308–14. Epub 2003/03/11. doi: 10.1177/153537020322800310 12626776.

39. Gottlieb E, Vander Heiden MG, Thompson CB. Bcl-x(L) prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Molecular and cellular biology. 2000;20(15):5680–9. Epub 2000/07/13. doi: 10.1128/mcb.20.15.5680-5689.2000 10891504; PubMed Central PMCID: PMC86039.

40. Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012;148(1–2):244–58. Epub 2012/01/24. doi: 10.1016/j.cell.2011.12.017 22265415; PubMed Central PMCID: PMC3511889.

41. Leroy B, Girard L, Hollestelle A, Minna JD, Gazdar AF, Soussi T. Analysis of TP53 mutation status in human cancer cell lines: a reassessment. Hum Mutat. 2014;35(6):756–65. Epub 2014/04/05. doi: 10.1002/humu.22556 24700732; PubMed Central PMCID: PMC4451114.

42. Wang Z, Sun Y. Targeting p53 for Novel Anticancer Therapy. Transl Oncol. 2010;3(1):1–12. Epub 2010/02/19. doi: 10.1593/tlo.09250 20165689; PubMed Central PMCID: PMC2822448.

43. Lane D, Levine A. p53 Research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol. 2010;2(12):a000893. Epub 2010/05/14. doi: 10.1101/cshperspect.a000893 20463001; PubMed Central PMCID: PMC2982174.

44. Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 1998;12(19):2973–83. Epub 1998/10/09. doi: 10.1101/gad.12.19.2973 9765199.

45. Ko LJ, Prives C. p53: puzzle and paradigm. Genes Dev. 1996;10(9):1054–72. Epub 1996/05/01. doi: 10.1101/gad.10.9.1054 8654922.

46. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88(3):323–31. Epub 1997/02/07. doi: 10.1016/s0092-8674(00)81871-1 9039259.

47. Jin S, Levine AJ. The p53 functional circuit. Journal of cell science. 2001;114(Pt 23):4139–40. Epub 2001/12/12. 11739646.

48. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, et al. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994;9(6):1799–805. Epub 1994/06/01. 8183579.

49. Miyashita T, Reed JC. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 1995;80(2):293–9. Epub 1995/01/27. doi: 10.1016/0092-8674(95)90412-3 7834749.

50. Harn HJ, Ho LI, Liu CA, Liu GC, Lin FG, Lin JJ, et al. Down regulation of bcl-2 by p53 in nasopharyngeal carcinoma and lack of detection of its specific t(14;18) chromosomal translocation in fixed tissues. Histopathology. 1996;28(4):317–23. Epub 1996/04/01. doi: 10.1046/j.1365-2559.1996.d01-431.x 8732340.

51. Miyashita T, Harigai M, Hanada M, Reed JC. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 1994;54(12):3131–5. Epub 1994/06/15. 8205530.

52. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75(4):817–25. Epub 1993/11/19. doi: 10.1016/0092-8674(93)90500-p 8242752.

53. Chan TA, Hwang PM, Hermeking H, Kinzler KW, Vogelstein B. Cooperative effects of genes controlling the G(2)/M checkpoint. Genes Dev. 2000;14(13):1584–8. Epub 2000/07/11. 10887152; PubMed Central PMCID: PMC316737.

54. Crowe DL, Sinha UK. p53 apoptotic response to DNA damage dependent on bcl2 but not bax in head and neck squamous cell carcinoma lines. Head Neck. 2006;28(1):15–23. Epub 2005/11/23. doi: 10.1002/hed.20319 16302195.

55. Kokontis JM, Wagner AJ, O'Leary M, Liao S, Hay N. A transcriptional activation function of p53 is dispensable for and inhibitory of its apoptotic function. Oncogene. 2001;20(6):659–68. Epub 2001/04/21. doi: 10.1038/sj.onc.1204139 11313999.

56. He M, Rennie PS, Dragowska V, Nelson CC, Jia W. A mutant P53 can activate apoptosis through a mechanism distinct from those induced by wild type P53. FEBS Lett. 2002;517(1–3):151–4. Epub 2002/06/14. doi: 10.1016/s0014-5793(02)02609-1 12062426.

57. Rahman M, Hasan MR. Cancer Metabolism and Drug Resistance. Metabolites. 2015;5(4):571–600. Epub 2015/10/06. doi: 10.3390/metabo5040571 26437434; PubMed Central PMCID: PMC4693186.

58. Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013;4:e532. Epub 2013/03/09. doi: 10.1038/cddis.2013.60 23470539; PubMed Central PMCID: PMC3613838.

59. Hultsch S, Kankainen M, Paavolainen L, Kovanen RM, Ikonen E, Kangaspeska S, et al. Association of tamoxifen resistance and lipid reprogramming in breast cancer. BMC Cancer. 2018;18(1):850. Epub 2018/08/26. doi: 10.1186/s12885-018-4757-z 30143015; PubMed Central PMCID: PMC6109356.

60. Kim MP, Gallick GE. Gemcitabine resistance in pancreatic cancer: picking the key players. Clin Cancer Res. 2008;14(5):1284–5. Epub 2008/03/05. doi: 10.1158/1078-0432.CCR-07-2247 18316544.

61. Liscovitch M, Lavie Y. Multidrug resistance: a role for cholesterol efflux pathways? Trends Biochem Sci. 2000;25(11):530–4. Epub 2000/11/21. doi: 10.1016/s0968-0004(00)01668-6 11084360.

Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression—An in vitro study

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