MiR-33a and statins collaboratively reduce the proliferative capacity of prostate cancer cells
MiR-33a and statins collaboratively reduce the proliferative capacity of prostate cancer cells
Objective: Prostate cancer (PCa) is one of the leading causes of cancer deaths among men in the developedcountries. 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 andprogression.In this study, we aimed at investigating the collaborative roles of cholesterol analogs, cholesterolloweringdrugs, and miR-33a, which is an important microRNA involved in regulation of cholesterolmetabolism,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 andanchorage independent growthcapacity of PCa cells using Cell Counting Kit-8, Matrigel invasion, and softagar assays, respectively.Results: We show that cholesterol analogs significantly promoted proliferative, invasive, and clonogenicpotential of PCa cells, while cholesterol loweringstatins demonstrated opposite effects. Moreover, LDL and25-HC reversed the tumor suppressive potential of miR-33a and statin treatment promoted the proliferationinhibitory effect of miR-33a on PCa cells.Conclusions:We demonstrated that statins inhibited the cellular phenotypes associated with PCa progressionand miR-33a treatment strengthens the impacts of statins on cellular proliferation. These findings suggest thatstatins alone and together with miR-33a might be a useful tool for effective and successful eradication of PCacells.
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- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Murtola TJ, Tammela TL, Lahtela J, Auvinen A. Cholesterollowering
drugs and prostate cancer risk: a population-based case-control
study. Cancer Epidemiol Biomarkers Prev 2007;16:2226-32.
- 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.
- 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.
- Ono K. Functions of microRNA-33a/b and microRNA therapeutics.
J Cardiol 2016;67:28-33.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Bommer GT, MacDougald OA. Regulation of lipid homeostasis by
the bifunctional SREBF2-miR33a locus. Cell Metab 2011;13:241-7.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, et
al. MicroRNA-33 encoded by an intron of sterol regulatory elementbinding
protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci
U S A 2010;107:17321-6.
- 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.
- 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.
- Barh D, Malhotra R, Ravi B, Sindhurani P. MicroRNA let-7: an
emerging next-generation cancer therapeutic. Curr Oncol 2010;17:70-
80.
- 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 BRDIM.
PLoS One 2012;7:e33729.