Year 2018, Volume 4 , Issue 4, Pages 266 - 274 2018-10-04

MiR-33a and statins collaboratively reduce the proliferative capacity of prostate cancer cells

Ömer Faruk Karataş [1] , Michael Ittmann [2]

Objectives: Prostate cancer (PCa) is one of the leading causes of cancer deaths among men in the developed countries. Accumulating data suggests a high-cholesterol Western diet as an important risk factor for PCa. Besides,significant evidencesassociate increased serum cholesterol levels with PCa development and progression.In this study, we aimed at investigating the collaborative roles of cholesterol analogs, cholesterol-lowering drugs, and miR-33a, which is an important microRNA involved in regulation of cholesterol metabolism,on the cellular phenotypes associated with PCa progression.

Methods: We evaluated the effects of low-density lipoprotein (LDL) cholesterol, 25-hydroxycholesterol (25-HC), mevastatin and simvastatin on their ownand together with miR-33a on the proliferation, invasion and anchorage independent growthcapacity of PCa cells using Cell Counting Kit-8, Matrigel invasion, and soft agar assays, respectively.

Results: We show that cholesterol analogs significantly promoted proliferative, invasive, and clonogenic potential of PCa cells, while cholesterol loweringstatins demonstrated opposite effects. Moreover, LDL and 25-HC reversed the tumor suppressive potential of miR-33a and statin treatment promoted the proliferation inhibitory effect of miR-33a on PCa cells.

Conclusions: We demonstrated that statins inhibited the cellular phenotypes associated with PCa progression and miR-33a treatment strengthens the impacts of statins on cellular proliferation. These findings suggest that statins alone and together with miR-33a might be a useful tool for effective and successful eradication of PCa cells. 

Prostate cancer, microRNA, miR-33a, cholesterol, sttatins
  • [1] Yang B, Liao GQ, Wen XF, Chen WH, Cheng S, Stolzenburg JU, et al. Nuclear magnetic resonance spectroscopy as a new approach for improvement of early diagnosis and risk stratification of prostate cancer. J Zhejiang Univ Sci B 2017;18:921-33.
  • [2] Brookman-Amissah N, Nariculam J, Freeman A, Willamson M, Kirby RS, Masters JR, et al. Allelic imbalance at 13q14.2 approximately q14.3 in localized prostate cancer is associated with early biochemical relapse. Cancer Genet Cytogenet 2007;179:118-26.
  • [3] Barron N, Keenan J, Gammell P, Martinez VG, Freeman A, Masters JR, et al. Biochemical relapse following radical prostatectomy and miR-200a levels in prostate cancer. Prostate 2012;72:1193-9.
  • [4] Bhatnagar N, Li X, Padi SK, Zhang Q, Tang MS, Guo B. Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Cell Death Dis 2010;1:e105.
  • [5] Masko EM, Alfaqih MA, Solomon KR, Barry WT, Newgard CB, Muehlbauer MJ, et al. Evidence for feedback regulation following cholesterol lowering therapy in a prostate cancer xenograft model. Prostate 2017;77:446-57.
  • [6] Van Hemelrijck M, Walldius G, Jungner I, Hammar N, Garmo H, Binda E, et al. Low levels of apolipoprotein A-I and HDL are associated with risk of prostate cancer in the Swedish AMORIS study. Cancer Causes Control 2011;22:1011-9.
  • [7] Farwell WR, D'Avolio LW, Scranton RE, Lawler EV, Gaziano JM. Statins and prostate cancer diagnosis and grade in a veterans population. J Natl Cancer Inst 2011;103:885-92.
  • [8] Mondul A, Weinstein S, Virtamo J, Albanes D. Serum total and HDL cholesterol and risk of prostate cancer. Cancer Causes Control 2011;22:1545-52.
  • [9] Allott EH, Howard LE, Cooperberg MR, Kane CJ, Aronson WJ, Terris MK, et al. Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. BJU Int 2014;114:661-6.
  • [10] Dillard PR, Lin MF, Khan SA. Androgen-independent prostate cancer cells acquire the complete steroidogenic potential of synthesizing testosterone from cholesterol. Mol Cell Endocrinol 2008;295:115-20.
  • [11] Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Cholesterol-lowering drugs and prostate cancer risk: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2007;16:2226-32.
  • [12] Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ. The risk of cancer in users of statins. J Clin Oncol 2004;22:2388-94.
  • [13] Platz EA, Leitzmann MF, Visvanathan K, Rimm EB, Stampfer MJ, Willett WC, et al. Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst 2006;98:1819-25.
  • [14] Ono K. Functions of microRNA-33a/b and microRNA therapeutics. J Cardiol 2016;67:28-33.
  • [15] Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010;328:1566-9.
  • [16] Karatas O, Wang J, Shao L, Ozen M, Zhang Y, Creighton C, Ittmann M. miR-33a is a tumor suppressor microRNA that is decreased in prostate cancer. Oncotarget 2017;8:60243-56.
  • [17] Kuo PL, Liao SH, Hung JY, Huang MS, Hsu YL. MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein. Biochim Biophys Acta 2013;1830:3756-66.
  • [18] Zhang C, Zhang Y, Ding W, Lin Y, Huang Z, Luo Q. MiR-33a suppresses breast cancer cell proliferation and metastasis by targeting ADAM9 and ROS1. Protein Cell 2015;6:881-9.
  • [19] Liang C, Yu XJ, Guo XZ, Sun MH, Wang Z, Song Y, et al. MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine. Oncotarget 2015;6:14440-55.
  • [20] Zhang J, Wang D, Xiong J, Chen L, Huang J. MicroRNA-33a-5p suppresses growth of osteosarcoma cells and is downregulated in human osteosarcoma. Oncol Lett 2015;10:2135-41.
  • [21] Zhou J, Xu D, Xie H, Tang J, Liu R, Li J, et al. miR-33a functions as a tumor suppressor in melanoma by targeting HIF-1α. Cancer Biol Ther 2015;16:846-55.
  • [22] Kang J, Kim W, Lee S, Kwon D, Chun J, Son B, et al. TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation. Oncogene 2017;36:1585-96.
  • [23] Yang L, Yang J, Li J, Shen X, Le Y, Zhou C, et al. MircoRNA-33a inhibits epithelial-to-mesenchymal transition and metastasis and could be a prognostic marker in non-small cell lung cancer. Sci Rep 2015;5:13677.
  • [24] Bommer GT, MacDougald OA. Regulation of lipid homeostasis by the bifunctional SREBF2-miR33a locus. Cell Metab 2011;13:241-7.
  • [25] Krycer JR, Kristiana I, Brown AJ. Cholesterol homeostasis in two commonly used human prostate cancer cell-lines, LNCaP and PC-3. PLoS One 2009;4:e8496.
  • [26] Yokomizo A, Shiota M, Kashiwagi E, Kuroiwa K, Tatsugami K, Inokuchi J, et al. Statins reduce the androgen sensitivity and cell proliferation by decreasing the androgen receptor protein in prostate cancer cells. Prostate 2011;71:298-304.
  • [27] Schnoeller TJ, Jentzmik F, Schrader AJ, Steinestel J. Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness. Oncotarget 2017;8:47110-20.
  • [28] Almutairi F, Peterson TC, Molinari M, Walsh MJ, Alwayn I, Peltekian KM. Safety and effectiveness of ezetimibe in liver transplant recipients with hypercholesterolemia. Liver Transpl 2009;15:504-8.
  • [29] Kitahara CM, Berrington de González A, Freedman ND, Huxley R, Mok Y, Jee SH, et al. Total cholesterol and cancer risk in a large prospective study in Korea. J Clin Oncol 2011;29:1592-8.
  • [30] Hamilton RJ, Goldberg KC, Platz EA, Freedland SJ. The influence of statin medications on prostate-specific antigen levels. J Natl Cancer Inst 2008;100:1511-8.
  • [31] Zheng X, Cui XX, Avila GE, Huang MT, Liu Y, Patel J, et al. Atorvastatin and celecoxib inhibit prostate PC-3 tumors in immunodeficient mice. Clin Cancer Res 2007;13(18 Pt 1):5480-7.
  • [32] Zheng X, Cui XX, Gao Z, Zhao Y, Lin Y, Shih WJ, et al. Atorvastatin and celecoxib in combination inhibits the progression of androgen-dependent LNCaP xenograft prostate tumors to androgen independence. Cancer Prev Res (Phila) 2010;3:114-24.
  • [33] Murtola TJ, Syvälä H, Pennanen P, Bläuer M, Solakivi T, Ylikomi T, et al. The importance of LDL and cholesterol metabolism for prostate epithelial cell growth. PLoS One 2012;7:e39445.
  • [34] Ingersoll MA, Miller DR, Martinez O, Wakefield CB, Hsieh KC, et al. Statin derivatives as therapeutic agents for castration-resistant prostate cancer. Cancer Lett 2016;383:94-105.
  • [35] Gonçalves I, Cherfan P, Söderberg I, Nordin Fredrikson G, Jonasson L. Effects of simvastatin on circulating autoantibodies to oxidized LDL antigens: relation with immune stimulation markers. Autoimmunity 2009;42:203-8.
  • [36] Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, et al. Inhibition of epidermal growth factor-induced RhoA translocation and invasion of human pancreatic cancer cells by 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors. Cancer Res 2001;61:4885-91.
  • [37] Nübel T, Dippold W, Kleinert H, Kaina B, Fritz G. Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and attenuates tumor cell adhesion. FASEB J 2004;18:140-2.
  • [38] Yang L, Egger M, Plattner R, Klocker H, Eder IE. Lovastatin causes diminished PSA secretion by inhibiting AR expression and function in LNCaP prostate cancer cells. Urology 2011;77:1508.e1501-1507.
  • [39] Wong YN, Ferraldeschi R, Attard G, de Bono J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat Rev Clin Oncol 2014;11:365-76.
  • [40] Gordon JA, Midha A, Szeitz A, Ghaffari M, Adomat HH, Guo Y, et al. Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts. Prostate Cancer Prostatic Dis 2016;19:21-7.
  • [41] Locke JA, Guns ES, Lubik AA, Adomat HH, Hendy SC, Wood CA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008;68:6407-15.
  • [42] Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al.; Collaboration CTTC. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
  • [43] Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, et al. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 2010;328:1566-9.
  • [44] Gerin I, Clerbaux LA, Haumont O, Lanthier N, Das AK, Burant CF, et al. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem 2010;285:33652-61.
  • [45] Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, et al. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci U S A 2010;107:17321-6.
  • [46] Marquart TJ, Allen RM, Ory DS, Baldán A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci U S A 2010;107:12228-32.
  • [47] Nadiminty N, Tummala R, Lou W, Zhu Y, Shi XB, Zou JX, et al. MicroRNA let-7c is downregulated in prostate cancer and suppresses prostate cancer growth. PLoS One 2012;7:e32832.
  • [48] Barh D, Malhotra R, Ravi B, Sindhurani P. MicroRNA let-7: an emerging next-generation cancer therapeutic. Curr Oncol 2010;17:70-80.
  • [49] Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One 2012;7:e33729.
Primary Language en
Subjects Health Care Sciences and Services
Journal Section Original Articles

Author: Ömer Faruk Karataş (Primary Author)
Country: Turkey

Author: Michael Ittmann
Institution: Department of Pathology & Immunology, Michael E. DeBakey Dept. of Veterans Affairs Medical Center, Houston, TX
Country: United States


Publication Date : October 4, 2018

EndNote %0 The European Research Journal MiR-33a and statins collaboratively reduce the proliferative capacity of prostate cancer cells %A Ömer Faruk Karataş , Michael Ittmann %T MiR-33a and statins collaboratively reduce the proliferative capacity of prostate cancer cells %D 2018 %J The European Research Journal %P -2149-3189 %V 4 %N 4 %R doi: 10.18621/eurj.380619 %U 10.18621/eurj.380619