Biopolym. Cell. 2018; 34(6):445-460.
Biomedicine
Expression patterns of genes that regulate lipid metabolism in prostate tumors
1Gerashchenko G. V., 2Kononenko O. A., 3Bondarenko Yu. M., 2Stakhovsky E. O., 1, 4Kashuba V. I.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
  2. National Cancer Institute
    33/43, Lomonosova Str., Kyiv, Ukraine, 03022
  3. State Institution «Institute of Urology of NAMS of Ukraine»
    9-a, Yu. Kotsubyns'koho Str., Kyiv, Ukraine, 04053
  4. Karolinska Institutet
    Stockholm SE-171 77, Sweden

Abstract

Aim. To assess relative expression (RE) levels of genes involved in lipid metabolism in prostate tumors. To define clinically significant specific alterations on the basis of the expression pattern. Methods. RE levels were analyzed in 37 samples of prostate cancer tissues by quantitative RT-PCR. The tumors were of a different Gleason score (GS) and various stages; the paired conventionally normal prostate tissue (CNT) samples and 20 samples of prostate adenomas were also analyzed. Results. Increased RE levels of FASN and COX2 were found in an adenocarcinoma group and in adenocarcinomas with GS=7 compared to the adenoma group. Four genes, namely FASN, LDLR, HMGCR and COX2, demonstrated significant RE alterations in the adenocarcinoma groups at different stages compared to the adenoma and CNT groups. Expression of three genes (LDLR, HMGCR, COX2) showed a negative correlation with stage and GS in the adenocarcinoma group. For FASN, LDLR, HMGCR, several positive correlations of RE with levels of the epithelial cell markers were found. CPT1C and COX2 demonstrated positive correlations of RE with expression of mesenchymal, fibroblast and inflammation markers in the adenocarcinoma group. Conclusions. The studied genes controlling lipid metabolism showed differential RE in prostate cancer samples. RE levels of FASN, HMGCR and COX2 might be used as markers of sensitivity and efficacy of inhibitory drugs. Further studies are needed to confirm these data in a larger patient cohort.
Keywords: prostate tumors, relative gene expression, lipid metabolism, pharmacological markers

References

[1] Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogenesis. 2016;5:e189.
[2] Cheng C, Geng F, Cheng X, Guo D. Lipid metabolism reprogramming and its potential targets in cancer. Cancer Commun (Lond). 2018;38(1):27.
[3] Santi A, Caselli A, Ranaldi F, Paoli P, Mugnaioni C, Michelucci E, Cirri P. Cancer associated fibroblasts transfer lipids and proteins to cancer cells through cargo vesicles supporting tumor growth. Biochim Biophys Acta. 2015;1853(12):3211-23.
[4] Ashida S, Kawada C, Inoue K. Stromal regulation of prostate cancer cell growth by mevalonate pathway enzymes HMGCS1 and HMGCR. Oncol Lett. 2017;14(6):6533-6542.
[5] Roy M, Kung HJ, Ghosh PM. Statins and prostate cancer: role of cholesterol inhibition vs. prevention of small GTP-binding proteins. Am J Cancer Res. 2011;1(4):542-61.
[6] Cruz PM, Mo H, McConathy WJ, Sabnis N, Lacko AG. The role of cholesterol metabolism and cholesterol transport in carcinogenesis: a review of scientific findings, relevant to future cancer therapeutics. Front Pharmacol. 2013;4:119.
[7] Casals N, Zammit V, Herrero L, Fadó R, Rodríguez-Rodríguez R, Serra D. Carnitine palmitoyltransferase 1C: From cognition to cancer. Prog Lipid Res. 2016;61:134-48.
[8] Roomets E, Kivelä T, Tyni T. Carnitine palmitoyltransferase I and Acyl-CoA dehydrogenase 9 in retina: insights of retinopathy in mitochondrial trifunctional protein defects. Invest Ophthalmol Vis Sci. 2008;49(4):1660-4.
[9] Sanchez-Macedo N, Feng J, Faubert B, Chang N, Elia A, Rushing EJ, Tsuchihara K, Bungard D, Berger SL, Jones RG, Mak TW, Zaugg K. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death Differ. 2013;20(4):659-68.
[10] Nath A, Chan C. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers. Sci Rep. 2016;6:18669.
[11] Schlaepfer IR, Rider L, Rodrigues LU, Gijón MA, Pac CT, Romero L, Cimic A, Sirintrapun SJ, Glodé LM, Eckel RH, Cramer SD. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther. 2014;13(10):2361-71.
[12] Kuhajda FP. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res. 2006;66(12):5977-80.
[13] Wu X, Daniels G, Lee P, Monaco ME. Lipid metabolism in prostate cancer. Am J Clin Exp Urol. 2014;2(2):111-20.
[14] Su CW, Zhang Y, Zhu YT. Stromal COX-2 signaling are correlated with colorectal cancer: A review. Crit Rev Oncol Hematol. 2016;107:33-38.
[15] Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res. 2015;8:105-18.
[16] Yang P, Cartwright CA, Li J, Wen S, Prokhorova IN, Shureiqi I, Troncoso P, Navone NM, Newman RA, Kim J. Arachidonic acid metabolism in human prostate cancer. Int J Oncol. 2012;41(4):1495-503.
[17] Hussain T, Gupta S, Mukhtar H. Cyclooxygenase-2 and prostate carcinogenesis. Cancer Lett. 2003;191(2):125-35.
[18] Lin DW, Nelson PS. The role of cyclooxygenase-2 inhibition for the prevention and treatment of prostate carcinoma. Clin Prostate Cancer. 2003;2(2):119-26.
[19] Flavin R, Peluso S, Nguyen PL, Loda M. Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol. 2010;6(4):551-62.
[20] Souchek JJ, Davis AL, Hill TK, Holmes MB, Qi B, Singh PK, Kridel SJ, Mohs AM. Combination Treatment with Orlistat-Containing Nanoparticles and Taxanes Is Synergistic and Enhances Microtubule Stability in Taxane-Resistant Prostate Cancer Cells. Mol Cancer Ther. 2017;16(9):1819-1830.
[21] Wright C, Iyer AKV, Kaushik V, Azad N. Anti-Tumorigenic Potential of a Novel Orlistat-AICAR Combination in Prostate Cancer Cells. J Cell Biochem. 2017, 118(11):3834-3845.
[22] Hajar R. Statins: past and present. Heart Views. 2011;12(3):121-7.
[23] Kang M, Lee KH, Lee HS, Jeong CW, Ku JH, Kim HH, Kwak C. Concurrent treatment with simvastatin and NF-κB inhibitor in human castration-resistant prostate cancer cells exerts synergistic anti-cancer effects via control of the NF-κB/LIN28/let-7 miRNA signaling pathway. PLoS One. 2017;12(9):e0184644.
[24] Zhang N, Li S, Hua H, Liu D, Song L, Sun P, Huang W, Tang Y, Zhao Y. Low density lipoprotein receptor targeted doxorubicin/DNA-Gold Nanorods as a chemo- and thermo-dual therapy for prostate cancer. Int J Pharm. 2016;513(1-2):376-386.
[25] Dheeraj A, Agarwal C, Schlaepfer IR, Raben D, Singh R, Agarwal R, Deep G. A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation. Hypoxia (Auckl). 2018;6:23-33.
[26] Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H, Andreeff M. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 2010;120(1):142-56.
[27] Ricciardi MR, Mirabilii S, Allegretti M, Licchetta R, Calarco A, Torrisi MR, Foà R, Nicolai R, Peluso G, Tafuri A. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood. 2015, 126(16):1925-9.
[28] Perroud HA, Alasino CM, Rico MJ, Mainetti LE, Queralt F, Pezzotto SM, Rozados VR, Scharovsky OG. Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response. Cancer Chemother Pharmacol. 2016;77(2):365-74.
[29] Gerashchenko GV, Mankovska OS, Dmitriev AA, Mevs LV, Rosenberg EE, Pikul MV, Marynychenko MV, Gryzodub OP, Stakhovsky EO, Kashuba VI. Expression of epithelial-mesenchymal transition-related genes in prostate tumours. Biopolym Cell. 2017, 33(5):335-55.
[30] Schmidt U, Fuessel S, Koch R, Baretton GB, Lohse A, Tomasetti S, Unversucht S, Froehner M, Wirth MP, Meye A. Quantitative multi-gene expression profiling of primary prostate cancer. Prostate. 2006;66(14):1521-34.
[31] Gerashchenko GV, Mevs LV, Chashchina LI, Pikul MV, Gryzodub OP, Stakhovsky EO, Kashuba VI. Expression of steroid and peptide hormone receptors, metabolic enzymes and EMT-related genes in prostate tumors in relation to the presence of the TMPRSS2/ERG fusion. Exp Oncol. 2018;40(2):101-8.
[32] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society. 1995, 57(1):289-300.
[33] Gerashchenko GV, Rynditch AV, Kashuba VI. Molecular profiling of prostate tumors. Dopov Nac Acad Nauk Ukr. 2018; 6: 113-9.
[34] New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products. 2018
[35] Stopsack KH, Gerke TA, Andrén O, Andersson SO, Giovannucci EL, Mucci LA, Rider JR. Cholesterol uptake and regulation in high-grade and lethal prostate cancers. Carcinogenesis. 2017;38(8):806-811.
[36] Kong Y, Cheng L, Mao F, Zhang Z, Zhang Y, Farah E, Bosler J, Bai Y, Ahmad N, Kuang S, Li L, Liu X. Inhibition of cholesterol biosynthesis overcomes enzalutamide resistance in castration-resistant prostate cancer (CRPC). J Biol Chem. 2018;293(37):14328-14341.
[37] FDA approves enzalutamide for castration-resistant prostate cancer. 2018, 07,