POLYAMINES AS NEW POTENTIAL BIOMARKERS FOR DIFFERENTIAL DIAGNOSIS OF PROSTATE CANCER AND ESTIMATION OF ITS AGGRESSIVENESS

Authors

  • S.P. Zaletok R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • O.O. Klenov R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • V.V. Bentrad R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • M.P. Prylutskyi R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • Yu.V. Vitruk National Cancer Institute of the Ministry of Health of Ukraine
  • E.O. Stakhovsky National Cancer Institute of the Ministry of Health of Ukraine
  • A.V. Timoshenko National Cancer Institute of the Ministry of Health of Ukraine

DOI:

https://doi.org/10.32471/exp-oncology.2312-8852.vol-44-no-2.17758

Keywords:

benign prostatic hyperplasia, polyamines, prostate cancer, spermine, tumor tissue

Abstract

Background: Prostate cancer (PCa) is one of the most common malignancies in older men. The study of tissue markers of PCa can provide information about the state of proliferation and apoptosis in tumors, the susceptibility of tumor cells to metastasis and the mechanisms of resistance to therapy, which, in turn, can help predict the course of the disease and develop personalized treatment. Polyamines (PAs) spermine, spermidine, putrescine are of particular interest in terms of PCa tissue markers. Aim: To investigate the levels of basic and acetylated forms of PAs in the postoperative samples of malignant and benign tumors of the human prostate and evaluate the possibility of their use for differential diagnosis and assessment of the PCa aggressiveness. Object and Methods: 57 postoperative tumor samples from patients with prostate adenocarcinoma of different Gleason score (GS) and clinical stage (T1–T4) and 20 samples of tumors from patients with benign prostate hyperplasia (BPH) were studied. The content of PAs was determined by high performance liquid chromatography. Results: Among the studied PAs, the most significant difference between PCa and BPH was observed for spermine (Spm). The level of Spm in PCa samples was 16 times lower than in BPH samples (p < 0.01). We did not find a significant dependence of PAs levels, including Spm, on the clinical stage. The association between the Spm level and the GS was established. The indolent (GS6) tumors were characterized by the highest Spm level while in the most aggressive (GS9 and GS10) tumors Spm content was the lowest. Conclusions: A sharp decrease in Spm levels is probably a characteristic feature of prostate malignant tumors. The obtained results indicate an association of Spm levels in tumors with the GS. This may indicate Spm involvement in the formation of the aggressiveness of PCa. The results of the study can be further used for differential diagnosis of prostate tumors and for assessing the aggressiveness of PCa.

References

Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68: 394–424. https://doi.org/10.3322/caac.21492

Fedorenko Z, Goulak L, Gourokh Ye, et al. Cancer in Ukraine, 2020–2021. Incidence, mortality, prevalence and other relevant statistics. Bull Natl Cancer Reg Ukr; Kyiv, 2020; 23. Available at http://www.ncru.inf.ua/ publications/BULL_23/index_e.htm

Stakhovsky EA, Fedorenko ZP, Vitruk YuV, et al. Prostate cancer screening. Clin Oncol 2016; 1: 50–3 (in Russian). https://www.clinicaloncology.com.ua/ article/15838/skrining-raka-predstatelnoj-zhelezy.

Lin Y, Zhao X, Miao Z, et al. Data-driven translational prostate cancer research: from biomarker discovery to clinical decision. J Transl Med 2020; 18: 119–36. https://doi.org/10.1186/s12967-020-02281-4

Bernal-Soriano MC, Parker LA, López-Garrigos M, et al. Factors associated with false negative and false positive results of prostate-specific antigen (PSA) and the impact on patient health: Cohort study protocol. Medicine 2019; 98: e17451. https://doi.org/10.1097/MD.0000000000017451

Saini S. PSA and beyond: alternative prostate cancer biomarkers. Cell Oncol 2016; 39: 97–106. https://doi.org/10.1007/s13402-016-0268-6

Kelly RS, Vander Heiden MG, Giovannucci E, et al. Metabolomic biomarkers of prostate cancer: prediction, diagnosis, progression, prognosis, and recurrence. Cancer Epidemiol Biomarkers Prev 2016; 25: 887–907. https://doi.org/10.1158/1055-9965.EPI-15-1223

Kdadra M, Höckner S, Leung H, et al. Metabolomics biomarkers of prostate cancer: a systematic review. Diagnostics 2019; 9: 21–65. https://doi.org/10.3390/diagnostics9010021

Lloyd SM, Arnold J, Sreekumar A. Metabolomic profiling of hormone-dependent cancers: a bird’s eye view. Trends Endocrinol Metab 2015; 26: 477–85. https://doi.org/10.1016/j.tem.2015.07.001

Tessem MB, Bertilsson H, Angelsen А, et al. A balanced tissue composition reveals new metabolic and gene expression markers in prostate cancer. PLOS ONE 2016; 11: e0153727. https://doi.org/10.1371/journal.pone.0153727

Chekhun VF, Lukianova NYu, Polishchuk LZ, et al. The role of lactoferrin expression in initiation and progression of most common hormone–dependent cancers. In: Hiroto S. Watanabe, ed. Horizons in Cancer Research, vol 66. New York: Nova Science Publishers, 2017: 51–85. https://novapublishers.com/shop/ horizons-in-cancer-research-volume-66/

Zadvornyi ТV, Borikun TV, Lukianova NYu, et al. Expression of miRNA–126, –205 AND –214 in benign and malignant neoplasms of the prostate gland: possible diagnostic and prognostic significance. Oncologiya 2019; 21: 10–6 (in Ukrainian). https://doi.org/10.32471/oncology.2663–7928.t–21–3–2019–g.7695

Zhylchuk YuV, Vozianov SO, Zadvornyi TV, et al. Prognostic value of cancer stem cell markers (CD44 and CD24) in combination with clinical and morphological characteristics of prostate cancer. IJSRM 2017; 6: 20–30. http://ijsrm.humanjournals.com/wp-content/ uploads/2017/06/2.Zhylchuk-Yu.V.-Zadvorny% D1%96-T.V.-Vozianov-S.O.-Sakalo-V.S.-Sakalo- A.V.-Grygorenko-V.N.-Lukianova-N.Yu_.-Chekhun-V.F..pdf

Renjie J, Yajun Yi, Yull FE, et al. NF-kB gene signature predicts prostate cancer progression. Cancer Res 2014; 74: 1–10. https://doi.org/10.1158/0008-5472.CAN-13-2543

Zaletok SP, Orlovsky OA, Gogol SV, et al. Molecular functions of polyamines in neoplastic growth and their role in control of the NF-κB transcription factor in experimental tumor cells. Likarska Sprava 2009; 1-2: 68–79 (in Ukrainian).

Zaletok SP. The role of polyamines in carcinogenesis and tumor growth. In: Oncology. Selected lectures for students and doctors ed. VF Chekhun. Kyiv, 2010: 354–70 (in Ukrainian).

Soda K. The mechanisms by which polyamines accelerate tumor spread. J Exp Clin Cancer Res 2011; 30: 95–104. https://doi.org/10.1186/1756-9966-30-95

Kusano T, Suzuki H. (eds.). Polyamines. A Universal Molecular Nexus for Growth, Survival, and Specialized Metabolism. Springer: Japan, 2015. 330 p. https://doi.org/10.1007/978-4-431-55212-3

Casero RA Jr, Murray Stewart T, Pegg AE. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat Rev Cancer 2018; 18: 681–95. https://doi.org/10.1038/s41568-018-0050-3

Li J, Meng Y, Wu X, et al. Polyamines and related signaling pathways in cancer. Cancer Cell Int 2020; 20: 539. https://doi.org/10.1186/s12935–020–01545–9

Childs AC, Mehta DJ, Gerner EW. Polyamine–dependent gene expression. Cell Mol Life Sci 2003; 60: 1394–406. https://doi.org/10.1007/s00018-003-2332-4

Palavan-Unsal, Aloglu-Senturk SM, Arısan D. The function of polyamine metabolism in prostate cancer. Exp Oncol 2006; 28: 178–86.

Andersen MK, Giskeødegård GF, Tessem M-B. Metabolic alterations in tissues and biofluids of prostate cancer patients. Curr Opin Endocr Metabol Res 2020; 10: 23–8. https://doi.org/10.1016/j.coemr.2020.02.003

Shukla-Dave A, Castillo-Martin M, Chen M, et al. Ornithine decarboxylase is sufficient for prostate tumorigenesis via androgen receptor signaling. Am J Pathol 2016; 186: 3131–45. https://doi.org/10.1016/j.ajpath.2016.08.021

Huang W, Eickhoff JC, Mehraein-Ghomi F, et al. Expression of spermidine/spermine N1-acetyl transferase (SSAT) in human prostate tissues is related to prostate cancer progression and metastasis. Prostate 2015; 75: 1150–9. https://doi.org/10.1002/pros.22996

Zabala-Letona A, Arruabarrena-Aristorena A, Martín-Martín N, et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 2017; 547: 109–13. https://doi.org/10.1038/nature22964

Smith R, Litwin M, Lu Y, Zetter B. Identification of an endogenous inhibitor of prostate carcinoma cell growth. Nature Med 1995; 1: 1040–5. https://doi.org/10.1038/nm1095-1040

Koike C, Chao DT, Zetter BR. Sensitivity to polyamine-induced growth arrest correlates with antizyme induction in prostate carcinoma cells. Cancer Res 1999; 59: 6109–12. PMID: 10626799

Simoneau AR, Gerner EW, Nagle R, et al. The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: results of a year-long phase IIb randomized placebo-controlled chemoprevention trial. Cancer Epidemiol Biomarkers Prev 2008; 17: 292–9. https://doi.org/10.1158/1055-9965.EPI-07-0658

Affronti HC, Rowsam AM, Pellerite AJ, et al. Pharmacological polyamine catabolism upregulation with methionine salvage pathway inhibition as an effective prostate cancer therapy. Nat Commun 2020; 11: 52–67. https://doi.org/10.1038/s41467-019-13950-4

Sun L, Yang J, Qin Y, et al. Discovery and antitumor evaluation of novel inhibitors of spermine oxidase. J Enz Inhib Med Chem 2019; 34: 1140–51. https://doi.org/10.1080/14756366.2019.1621863

Gerbaut L. Determination of erythrocytic polyamines by reversed-phase liquid chromatography. Clin Chem 1991; 37: 2117–20. PMID: 1764787

McDunn JE, Li Z, Adam K-P, et al. Metabolomic signatures of aggressive prostate cancer. The Prostate 2013; 73: 1547–60. https://doi.org/10.1002/pros.22704

Peng Q, Wong CY-P, Cheuk IW, et al. The emerging clinical role of spermine in prostate cancer. Int J Mol Sci 2021; 22: 4382–402. https://doi.org/10.3390/ijms22094382

Battaglia V, DeStefano Shields C, Murray-Stewart T, et al. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention. Amino Acids 2014; 46: 511–9. https://doi.org/10.1007/s00726-013-1529-6

Bentrad VV, Zaletok SP, Klenov OO, et al. Gene expression of polyamine metabolism proteins in human prostate cancer and benign prostatic hyperplasia. Oncologiya 2020; 22: 32−5 (In Ukrainian). https://doi.org/10.32471/oncology.2663-7928.t-22-1-2020-g.8739

Giskeødegård GF, Bertilsson H, Selnæs KM, et al. Spermine and citrate as metabolic biomarkers for assessing prostate cancer aggressiveness. PLoS One 2013; 8: e62375. https://doi.org/10.1371/journal.pone.0062375

Braadland PR, Giskeødegård G, Sandsmark E, et al. Ex vivo metabolic fingerprinting identifies biomarkers predictive of prostate cancer recurrence following radical prostatectomy. Br J Cancer 2017; 117:1656–64. https://doi.org/10.1038/bjc.2017.346

Zaletok SP, Klenov OO, Gogol SV, et al. Blood and urine polyamines as new diagnostic markers of prostate cancer. Oncologiya 2019; 21: 219–24 (In Ukrainian). https://doi.org/10.32471/oncology.2663-7928.t-21-3-2019-g.7755

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Published

26.05.2023

How to Cite

Zaletok, S., Klenov, O., Bentrad, V., Prylutskyi, M., Vitruk, Y., Stakhovsky, E., & Timoshenko, A. (2023). POLYAMINES AS NEW POTENTIAL BIOMARKERS FOR DIFFERENTIAL DIAGNOSIS OF PROSTATE CANCER AND ESTIMATION OF ITS AGGRESSIVENESS. Experimental Oncology, 44(2), 148–154. https://doi.org/10.32471/exp-oncology.2312-8852.vol-44-no-2.17758

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