Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

Ifere,Godwin   O.; Desmond,Renee; Demark-Wahnefried,Wendy; Nagy,Tim   R.

doi:10.3892/ijo.2013.2057

Apolipoprotein E gene polymorphism influences aggressive behavior in prostate cancer cells by deregulating cholesterol homeostasis

Authors:
- Godwin O. Ifere
- Renee Desmond
- Wendy Demark-Wahnefried
- Tim R. Nagy
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Affiliations: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA, Division of Preventive Medicine, UAB, Birmingham, AL 35294, USA
Published online on: August 7, 2013 https://doi.org/10.3892/ijo.2013.2057
Pages: 1002-1010
Copyright: © Ifere et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

High circulating cholesterol and its deregulated homeostasis may facilitate prostate cancer progression. Genetic polymorphism in Apolipoprotein (Apo) E, a key cholesterol regulatory protein may effect changes in systemic cholesterol levels. In this investigation, we determined whether variants of the Apo E gene can trigger defective intracellular cholesterol efflux, which could promote aggressive prostate cancer. ApoE genotypes of weakly (non-aggressive), moderate and highly tumorigenic (aggressive) prostate cancer cell lines were characterized, and we explored whether the ApoE variants were associated with tumor aggressiveness generated by intracellular cholesterol imbalance, using the expression of caveolin-1 (cav-1), a pro-malignancy surrogate of cholesterol overload. Restriction isotyping of ApoE isoforms revealed that the non-aggressive cell lines carried ApoE ε3/ε3 or ε3/ε4 alleles, while the aggressive cell lines carried the Apoε2/ε4 alleles. Our data suggest a contrast between the non-aggressive and the aggressive prostate cancer cell lines in the pattern of cholesterol efflux and cav-1 expression. Our exploratory results suggest a relationship between prostate aggressiveness, ApoE isoforms and cholesterol imbalance. Further investigation of this relationship may elucidate the molecular basis for considering cholesterol as a risk factor of aggressive prostate tumors, and underscore the potential of the dysfunctional ApoE2/E4 isoform as a biomarker of aggressive disease.

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1.	Williams SD, Cook ED, Anderson KB and Hamilton SJ: Bridging the gap between populations: the challenge of reducing cancer disparities among African-American and other ethnic minority populations. US Oncol. 4:72–75. 2008.
2.	Ifere GO, Abebe F and Ananaba GA: Emergent trends in the reported incidence of prostate cancer in Nigeria. Clin Epidemiol. 4:19–32. 2012. View Article : Google Scholar : PubMed/NCBI
3.	Sakr WA: Prostatic intraepithelial neoplasia: A marker for high-risk groups and a potential target for chemoprevention. Eur Urol. 35:474–478. 1999. View Article : Google Scholar : PubMed/NCBI
4.	Bock CH, Powell I, Kittles RA, Hsing AW and Carpten J: Racial disparity in prostate cancer incidence, biochemical recurrence, and mortality. Prostate Cancer. 716178:1–2. 2011. View Article : Google Scholar : PubMed/NCBI
5.	Bigler SA, Pound CR and Zhou X: A retrospective study on pathological features and racial disparities in prostate cancer. Prostate Cancer. 2011:2394602011. View Article : Google Scholar : PubMed/NCBI
6.	Lee J, Demissie K, Lu SE and Rhoads GG: Cancer incidence among Korean-American immigrants in the United States and native Koreans of South Korea. Cancer Control. 14:78–85. 2007.PubMed/NCBI
7.	Ma RW and Chapman K: A systematic review of the effect of diet in prostate cancer prevention and treatment. J Hum Nutr Diet. 22:187–199. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Michaud DS, Augustsson K, Rimm EB, Stampfer MJ, Willet WC and Giovanucci E: A prospective study on intake of animal products and risk of prostate cancer. Cancer Causes Control. 12:557–567. 2001. View Article : Google Scholar : PubMed/NCBI
9.	Waddell WJ: Epidemiological studies and effects of environmental estrogens. Int J Toxicol. 17:173–191. 1998. View Article : Google Scholar
10.	Le Marchand L and Wilkens LR: Design considerations for genomic association studies: importance of gene-environment interactions. Cancer Epidemiol Biomarkers Prev. 17:263–267. 2008.PubMed/NCBI
11.	Nothlings U, Yamamoto JF, Wilkens LR, Murphy SP, Park SY, Henderson BE, Kolonel LN and Le Marchand L: Meat and heterocyclic amine intake, smoking, NAT1 and NAT2 polymorphisms, and colorectal cancer risk in the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 18:2097–2106. 2009. View Article : Google Scholar : PubMed/NCBI
12.	Wünsch Filho V and Zago MA: Modern cancer epidemiology research: genetic polymorphism and environment. Rev Saude Publica. 39:490–497. 2005.
13.	Finch CE and Stanford CB: Meat-adaptive genes and the evolution of slower aging in humans. Q Rev Biol. 79:3–50. 2004. View Article : Google Scholar : PubMed/NCBI
14.	Mahley RW: Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 240:622–630. 1988. View Article : Google Scholar : PubMed/NCBI
15.	Tziakas DN, Chalikias GK, Antonoglou CO, Veletza S, Tentes IK, Kortsaris AX, Hatseras DI and Kaski JC: Apolipoprotein E genotype and circulating interleukin-10 levels in patients with stable and unstable coronary artery disease. J Am Coll Cardiol. 48:2471–2481. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Leduc V, Domenger D, De Beaumont L, Lalonde D, Bélanger-Jasmin S and Poirier J: Function and comorbidities of apolipoprotein E in Alzheimer’s disease. Int J Alzheimers Dis. 2011:1–22. 2011.
17.	Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE and Stroehla BC: Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 155:487–495. 2002. View Article : Google Scholar : PubMed/NCBI
18.	Mahley RW and Rall SC Jr: Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet. 1:507–537. 2000. View Article : Google Scholar : PubMed/NCBI
19.	Moore RJ, Chamberlain RM and Khuri FR: Apolipoprotein E and the risk of breast cancer in African-American and non-Hispanic white women. A review. Oncology. 66:79–93. 2004. View Article : Google Scholar : PubMed/NCBI
20.	Kallio MJ, Salmenperä L, Siimes MA, Perheentupa J, Gylling H and Miettinen TA: Apolipoprotein E phenotype determines serum cholesterol in infants during both high-cholesterol breast feeding and low-cholesterol formula feeding. J Lipid Res. 38:759–764. 1997.PubMed/NCBI
21.	Berglund L: The APOE gene and diets - food (and drink) for thought. Am J Clin Nutr. 73:669–670. 2001.PubMed/NCBI
22.	Papaioannou I, Simmons JP and Owen JS: Targeted in situ gene correction of dysfunctional APOE alleles to produce atheroprotective plasma ApoE3 protein. Cardiol Res Pract. 2012:1487962012.PubMed/NCBI
23.	Kockx M, Jessup W and Kritharides L: Regulation of endogenous apolipoprotein E secretion by macrophages. Arterioscler Thromb Vasc Biol. 28:1060–1067. 2008. View Article : Google Scholar : PubMed/NCBI
24.	Huang ZH, Fitzgerald ML and Mazzone T: Distinct cellular loci for the ABCA1-dependent and ABCA1-independent lipid efflux mediated by endogenous apolipoprotein E expression. Arterioscler Thromb Vasc Biol. 26:157–162. 2006. View Article : Google Scholar : PubMed/NCBI
25.	Huang Y, von Eckardstein A, Wu S and Assmann G: Effects of the apolipoprotein E polymorphism on uptake and transfer of cell derived cholesterol in plasma. J Clin Invest. 96:2693–2701. 1995. View Article : Google Scholar : PubMed/NCBI
26.	Lane RM and Farlow MR: Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer’s disease. J Lipid Res. 46:949–968. 2005.
27.	Uittenbogaard A, Ying Y and Smart EJ: Characterization of a cytosolic heat-shock protein-caveolin chaperone complex. Involvement in cholesterol trafficking. J Biol Chem. 273:6525–6532. 1998. View Article : Google Scholar : PubMed/NCBI
28.	Liscum L and Munn NJ: Intracellular cholesterol transport. Biochim Biophys Acta. 1438:19–37. 1999. View Article : Google Scholar
29.	Li YC, Park MJ, Ye SK, Kim CW and Kim YN: Elevated levels of cholesterol-rich lipid rafts in cancer cells are correlated with apoptosis sensitivity induced by cholesterol-depleting agents. Am J Pathol. 168:1107–1118. 2006. View Article : Google Scholar : PubMed/NCBI
30.	Hixson JE and Vernier DT: Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J Lipid Res. 31:545–548. 1990.PubMed/NCBI
31.	Sankaranarayanan S, Kellner-Weibel G, de la Llera-Moya M, Phillips MC, Asztalos BF, Bittmam R and Rothblat GH: A sensitive assay for ABCA1-mediated cholesterol efflux using BODIPY-cholesterol. J Lipid Res. 52:2332–2340. 2011. View Article : Google Scholar : PubMed/NCBI
32.	Yue L and Mazzone T: Endogenous adipocyte apolipoprotein E is colocalized with caveolin at the adipocyte plasma membrane. J Lipid Res. 52:489–498. 2011. View Article : Google Scholar : PubMed/NCBI
33.	Nair HK, Rao KV, Aalinkeel R, Mahajan S, Chawda R and Schwartz SA: Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol. 11:63–69. 2004.PubMed/NCBI
34.	Saraon P, Musrap N, Cretu D, Karagiannis GS, Batruch I, Smith C, Drabovich AP, Trudel D, van der Kwast T, Morrissey C, Jarvi KA and Diamandis EP: Proteomic profiling of androgen-independent prostate cancer cell lines reveals a role for protein S during the development of high grade and castration-resistant prostate cancer. J Biol Chem. 287:34019–34031. 2012. View Article : Google Scholar
35.	Wang B, Yang Q, Ceniccola K, Bianco F, Andrawis R, Jarret T, Frazier H, Patierno SR and Lee NH: Androgen receptor-target gene in African American prostate cancer disparities. Prostate Cancer. 2013:7635692013. View Article : Google Scholar : PubMed/NCBI
36.	Kim DH and Wirtz D: Recapitulating cancer cell invasion in vitro. Proc Natl Acad Sci USA. 108:6693–6694. 2011. View Article : Google Scholar : PubMed/NCBI
37.	Hoosein NM: Neuroendocrine and immune mediators in prostate cancer progression. Front Biosci. 3:D1274–D1279. 1998.PubMed/NCBI
38.	Hara T, Miyazaki H, Lee A, Tran CP and Reiter RE: Androgen receptor and invasion in prostate cancer. Cancer Res. 68:1128–1135. 2008. View Article : Google Scholar : PubMed/NCBI
39.	Nomura DK, Lombardi DP, Chang JW, Niessen S, Ward AM, Long JZ, Hoover HH and Cravatt BF: Monoacylglycerol lipase exerts dual control over endocannabinoid and fatty acid pathways to support prostate cancer. Chem Biol. 18:846–856. 2011. View Article : Google Scholar : PubMed/NCBI
40.	Venanzoni MC, Giunta S, Murara GB, Storari L, Crescini C, Mazzucchelli R, Montironi R and Seth A: Apolipoprotein E expression in localized prostate cancers. Int J Oncol. 22:779–786. 2003.PubMed/NCBI
41.	Saadat M: Apolipoprotein E (ApoE) polymorphism and susceptibility to breast cancer: a meta-analysis. Cancer Res Treat. 44:121–126. 2012. View Article : Google Scholar : PubMed/NCBI
42.	Niemi M, Kervinen K, Kiviniemi H, Lukkarinen O, Kyllönen AP, Apaja-Sarkkinen M, Savolainen MJ, Kairaluoma MI and Kesäniemi YA: Apolipoprotein E phenotype, cholesterol and breast and prostate cancer. J Epidemiol Community Health. 54:938–939. 2000. View Article : Google Scholar : PubMed/NCBI
43.	Haapla K, Lehtimäki T, Ilveskoski E and Koivisto PA: Apolipoprotein E is not linked to locally recurrent hormone-refractory prostate cancer. Prostate Cancer Prostatic Dis. 3:107–109. 2000. View Article : Google Scholar : PubMed/NCBI
44.	Koivisto P, Visakorpi T, Rantala I and Isola J: Increased cell proliferation activity and decreased cell death are associated with the emergence of hormone-refractory recurrent prostate cancer. J Pathol. 183:51–56. 1997. View Article : Google Scholar : PubMed/NCBI
45.	Mostaghel EA, Solomon KR, Pelton K, Freeman MR and Montgomery RB: Impact of circulating cholesterol levels on growth and intratumoral androgen concentration of prostate tumors. PLoS One. 7:e300622012. View Article : Google Scholar : PubMed/NCBI
46.	Krimbou L, Denis M, Haidar B, Carrier M, Marci M and Genest J Jr: Molecular interactions between apoE and ABCA1: impact on apoE lipidation. J Lipid Res. 45:839–848. 2004. View Article : Google Scholar : PubMed/NCBI
47.	Cullen P, Cignarella A, Brennhausen B, Mohr S, Assmann G and Von Eckardstein A: Phenotype-dependent differences in apolipoprotein E metabolism and in cholesterol homeostasis in human monocyte-derived macrophages. J Clin Invest. 101:1670–1677. 1998. View Article : Google Scholar : PubMed/NCBI
48.	Murtola TJ, Syvälä H, Pennanen P, Bläuer M, Solakivi T, Ylikomi T and Tammela TL: The importance of LDL and cholesterol metabolism for prostate epithelial cell growth. PLoS One. 7:e394452012. View Article : Google Scholar : PubMed/NCBI
49.	Smith JD, Miyata M, Ginsberg M, Grigaux C, Shmookler E and Plump AS: Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein acceptors. J Biol Chem. 271:30647–30655. 1996. View Article : Google Scholar : PubMed/NCBI
50.	Hara M, Matsushima T, Satoh H, Iso-o N, Noto H, Togo M, Kimura S, Hashimoto Y and Tsukamoto K: Isoform-dependent cholesterol efflux from macrophages by apolipoprotein E is modulated by cell surface proteoglycan. Arterioscler Thromb Vasc Biol. 23:269–274. 2003. View Article : Google Scholar : PubMed/NCBI
51.	Karasinska JM and Hayden MR: Cholesterol metabolism in Huntington disease. Nat Rev Neurol. 7:561–572. 2011. View Article : Google Scholar : PubMed/NCBI
52.	Fernández-Hernando C, Yu J, Dávalos A, Prendergast J and Sessa WC: Endothelial-specific overexpression of caveolin-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol. 177:998–1003. 2010.PubMed/NCBI
53.	Cohen AW, Hnaska R, Schubert W and Lisanti MP: Role of caveolae and caveolins in health and disease. Physiol Rev. 84:1341–1379. 2004. View Article : Google Scholar : PubMed/NCBI
54.	Frank PG, Cheung MW, Pavlides S, Llaverias G, Park DS and Lisanti MP: Caveolin-1 and regulation of cellular cholesterol homeostasis. Am J Physiol Heart Circ Physiol. 291:H677–H686. 2006. View Article : Google Scholar : PubMed/NCBI
55.	Daniel EE, El-Yazbi A and Cho WJ: Caveolae and calcium handling, a review and a hypothesis. J Cell Mol Med. 10:529–544. 2006. View Article : Google Scholar : PubMed/NCBI
56.	Yang G, Truong LD, Wheeler TM and Thompson TC: Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker. Cancer Res. 59:5719–5723. 1999.PubMed/NCBI
57.	Thompson TC: Metastasis-related genes in prostate cancer: the role of caveolin-1. Cancer Metastasis Rev. 17:439–442. 1999. View Article : Google Scholar : PubMed/NCBI
58.	Williams TM, Hassan GS, Li J, Cohen AW, Medina F, Frank PG, Pestell RG, Di Vizio D, Loda M and Lisanti MP: Caveolin-1 promotes tumor progression in an autochthonous mouse model of prostate cancer. J Biol Chem. 280:25134–25145. 2005. View Article : Google Scholar : PubMed/NCBI
59.	Lin YC, Ma C, Hsu WC, Lo HF and Yang VC: Molecular interaction between caveolin-1 and ABCA1 on high-density lipoprotein-mediated cholesterol efflux in aortic endothelial cells. Cardiovasc Res. 75:575–583. 2007. View Article : Google Scholar
60.	Le Lay S, Rodriguez M, Jessup W, Rentero C, Li Q, Cartland S, Grewal T and Gaus K: Caveolin-1-mediated apolipoprotein A-I membrane binding sites are not required for cholesterol efflux. PLoS One. 6:e233532011.PubMed/NCBI