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1 Zinc can serve as a biomarker in PCa diagnosis and therapies. In future, developing some more efficient zinc detection strategies to achieve early PCa diagnosis, and targeting zinc signaling in PCa immunotherapies verified in clinic are urgently needed.
Guangchao Sui
 + 984 word(s) 984 2020-02-02 12:34:42 |
2 The authors are Dangdang Li and Guangchao Sui.
Guangchao Sui
 Meta information modification 984 2020-02-13 16:18:10 | |
3 format correct
Catherine Yang
 + 6 word(s) 990 2020-11-01 09:02:57 | |
4 reference
Mohammed Amine
 Meta information modification 990 2021-11-05 01:11:13 |

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Li, D.; Stovall, D.B.; Wang, W.; Sui, G.; Amine, M. Zinc Signaling in Prostate Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/293 (accessed on 17 November 2024).
Li D, Stovall DB, Wang W, Sui G, Amine M. Zinc Signaling in Prostate Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/293. Accessed November 17, 2024.
Li, Dangdang, Daniel B. Stovall, Wenmeng Wang, Guangchao Sui, Mohammed Amine. "Zinc Signaling in Prostate Cancer" Encyclopedia, https://encyclopedia.pub/entry/293 (accessed November 17, 2024).
Li, D., Stovall, D.B., Wang, W., Sui, G., & Amine, M. (2020, February 13). Zinc Signaling in Prostate Cancer. In Encyclopedia. https://encyclopedia.pub/entry/293
Li, Dangdang, et al. "Zinc Signaling in Prostate Cancer." Encyclopedia. Web. 13 February, 2020.
Zinc Signaling in Prostate Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/ijms21020667

Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer-related death among men worldwide. Despite progresses in early diagnosis and therapeutic strategies, prognosis for patients with advanced PCa remains poor. Therefore, it is necessary to develop novel strategies to prevent, diagnose and effectively treat PCa patients in clinic. Noteworthily, a unique feature of healthy prostate is its highest level of zinc content among all soft tissues in the human body, which dramatically decreases during prostate tumorigenesis. Here, we discuss clinical applications of zinc-containing compounds and proteins involved in PCa signaling pathways. Based on currently available studies, we conclude that zinc can serve as a biomarker in PCa diagnosis and therapies.

zinc signaling prostate cancer zinc transporter zinc finger diagnosis immunotherapy

1. Introduction

Significantly decreased zinc levels during prostate malignancy implicated its activities in inhibiting proliferation and metastasis of tumor cells and inducing cell death, which led to the development of zinc or its related compounds in diagnostic and therapeutic applications of PCa. Due to the controversies and inconsistent results regarding the effects of zinc supplementation on PCa among different laboratory research and epidemiologic studies[1][2][3][4][5][6][7][8], we will mainly discuss the applications of zinc and its associated proteins as they relate to clinical diagnosis of PCa in this section. Additionally, we will comment on immunotherapies targeting zinc signaling.

2. Clinical Applications of Zinc Signaling in PCa

In the clinic, currently prevailing tests of PCa diagnosis can be divided into two categories: traditional and modern methods. The traditional methods include digital rectal examination and blood PSA tests, while modern methods embrace targeted magnetic resonance imaging (MRI), ultrasound fusion prostate biopsy and conventional radiological imaging[9][10][11]. Each approach may have its own disadvantages in specificity, invasiveness or targeting accuracy, which restricts its applications to patients with specific types or stages of the disease[12][13].Fortunately, PCa is the only known prostatic disease associated with a substantial decrease of zinc levels[14]; neither prostatitis nor BPHexhibit this phenomenon[12][15], suggesting that zinc serves as an excellent candidate biomarker for PCa. Indeed, based on synthetic images generated from clinical data of zinc distributions, zinc-baseddiagnostics could represent an approach superior to the serum PSA test[13][16]. Recently, several groups developed in vivo imaging strategies to simultaneously probe zinc presence and detect PCa progression[12][13][17][18][19]. Ghosh et al. employed a novel fluorescent zinc sensor ZPP1 that could precisely bind two zinc ions to monitor cell malignant transformation in the TRAMP model and observed tumor progression related to decreasing fluorescence intensity in an age-dependent manner. This study is the first report of using altered zinc levels as an innate imaging biomarker for early PCa detection[13][20]. Due to the limitations of optical imaging[12], several groups attempted to optimize zinc measurement using MRI in the following years. Jordan et al. discovered a zinc-binding gadolinium using a paramagnetic contrast agent and used it to detect extracellular zinc by proton MRI following glucose-stimulated zinc secretion. This strategy let them differentiate healthy versus malignant mouse prostates, which could provide a novel and highly specific approach for PCa diagnosis[17]. More recently, using MRI based on 19F ion chemical exchange saturation transfer (iCEST) and TF-BAPTA as a fluorinated zinc probe, Yuan et al. was able to discriminate normal and malignant prostate cells with a 10-fold higher sensitivity than the method based on glucose-stimulated zinc secretion. The iCEST-MRI allowed them to observe over 300% gradual zinc decrease in the in vivo transition of normal PrECs to cancer cells[12]. This study is the first attempt to use the 19F iCEST-MRI as a diagnostic tool for in vivo zinc imaging. Since both iCEST and 19F MRI are clinically used, this approach possesses high translational potential for clinical diagnosis of PCa. Despite these promising research and preclinical data, further exploration needs to focus on developing zinc detection strategies with high specificity, sensitivity, and economic advantage to achieve early PCa diagnosis.

Noteworthily, decreased intraprostatic zinc levels generally coincide with significantly reduced expression of the zinc transporters ZIP1, ZIP2, ZIP3 and ZIP4, which represents an early step in PCa development[1][12][21][22][23]. Based on the impacts of altered expression of these zinc transporters on PCa cell growth and metastasis, the expression levels of ZIP1, ZIP2, ZIP3 and ZIP4 genes may also serve as potential biomarkers for early PCa diagnosis. Additionally, among the upstream regulators of ZIP1 (RREB-1 and microRNA-183-96-182), the proteins modulating key zinc signaling pathways (NF-κB, PI3K and MAPK), and ZF-containing TFs (AR, PLZF and SP1), many of them have been evaluated as or determined to be potential assistant biomarkers for PCa diagnosis. In our opinion, zinc status and the genes involved in zinc homeostasis could serve as an adjunctive measure to the traditional and modern methods of PCa diagnosis.

In the past decade, immunotherapy has proven to be an effective approach in the treatment of multiple cancer types, especially melanoma and non-small cell lung cancer[24][25][26]. For PCa, immunotherapies using immune checkpoint inhibition, PSA vaccines and dendritic cell-based strategies have been intensively tested in clinical trials[27]. Ample evidence demonstrated zinc’s contribution to the maintenance of host systemic immune system, and thus, its moderate levels could decrease inflammation and oxidative stress[28][29][30][31]. Generally, zinc at its physiological levels is essential to the growth, differentiation and biological function of various immune cells, including macrophages, dendritic cells, neutrophils, mast cells, T cells and B cells[32][33][34][35][36][37]. On the other hand, zinc deficiency leads to impaired immune response and an increased risk of inflammation and tumorigenesis[29][33][38]. Consistently, moderate zinc supplementation can restore or even improve host defense and reduce both morbidity and mortality of various diseases, including cancers[39][40][41]. Therefore, targeting zinc signaling to prevent immune escape of tumor cells and promote immune cells to eradicate cancers represents a logical and promising strategy in the treatments of PCa patients. However, due to the high complexity of the immune microenvironment and high  heterogeneity of antitumor immune responses[27][42][43], the application of targeting zinc signaling in immunotherapies has not been tested in either preclinical models or the patients of PCa.

References

  1. Kolenko, V.; Teper, E.; Kutikov, A.; Uzzo, R.; Zinc and zinc transporters in prostate carcinogenesis. Nat. Rev. Urol. 2013, 10, 219–226, 10.1038/nrurol.2013.43.
  2. Singh, C.K.; Pitschmann, A.; Ahmad, N.; Resveratrol-zinc combination for prostate cancer management. Cell Cycle 2014, 13, 1867–1874, 10.4161/cc.29334.
  3. Banudevi, S.; Elumalai, P.; Arunkumar, R.; Senthilkumar, K.; Gunadharini, D.N.; Sharmila, G.; Arunakaran, J.; Chemopreventive effects of zinc on prostate carcinogenesis induced by N-methyl-N-nitrosourea and testosterone in adult male Sprague-Dawley rats. Cancer Res. Clin. Oncol. 2011, 137, 677–686, 10.1007/s00432-010-0926-4.
  4. Prasad, A.S.; Mukhtar, H.; Beck, F.W.; Adhami, V.M.; Siddiqui, I.A.; Din, M.; Hafeez, B.B.; Kucuk, O.; Dietary zinc and prostate cancer in the TRAMP mouse model. Med. Food 2010, 13, 70–76, 10.1089/jmf.2009.0042.
  5. Feng, P.; Li, T.L.; Guan, Z.X.; Franklin, R.B.; Costello, L.C.; Effect of zinc on prostatic tumorigenicity in nude mice. Ann. N. Y. Acad. Sci. 2003, 1010, 316–320, 10.1196/annals.1299.056.
  6. Gallus, S.; Foschi, R.; Negri, E.; Talamini, R.; Franceschi, S.; Montella, M.; Ramazzotti, V.; Tavani, A.; Dal Maso, L.; La Vecchia, C.; et al. Dietary zinc and prostate cancer risk: A case-control study from Italy. Eur. Urol. 2007, 52, 1052–1056, 10.1016/j.eururo.2007.01.094.
  7. Leitzmann, M.F.; Stampfer, M.J.; Wu, K.; Colditz, G.A.; Willett, W.C.; Giovannucci, E.L.; Zinc supplement use and risk of prostate cancer. J. Natl. Cancer Inst. 2003, 95, 1004–1007, 10.1093/jnci/95.13.1004.
  8. Banudevi, S.; Elumalai, P.; Sharmila, G.; Arunkumar, R.; Senthilkumar, K.; Arunakaran, J.; Protective e ect of zinc on N-methyl-N-nitrosourea and testosterone-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley rats. Exp. Biol. Med. 2011, 236, 1012–102, 10.1258/ebm.2011.010392.
  9. Fitzsimons, N.J.; Sun, L.; Moul, J.W.; Medical technologies for the diagnosis of prostate cancer. Expert Rev. Med. Devices 2007, 4, 227–239, 10.1586/17434440.4.2.227.
  10. Hoeks, C.M.; Hambrock, T.; Yakar, D.; Hulsbergen-van de Kaa, C.A.; Feuth, T.; Witjes, J.A.; Futterer, J.J.; Barentsz, J.O.; Transition zone prostate cancer: Detection and localization with 3-T multiparametric MR imaging. Radiology 2013, 266, 207–217, 10.1148/radiol.12120281.
  11. Costa, D.N.; Pedrosa, I.; Donato, F., Jr.; Roehrborn, C.G.; Rofsky, N.M.; MR Imaging-Transrectal US Fusion for Targeted Prostate Biopsies: Implications for Diagnosis and Clinical Management. Radiographics 2015, 35, 696–708, 10.1148/rg.2015140058.
  12. Yuan, Y.; Wei, Z.; Chu, C.; Zhang, J.; Song, X.; Walczak, P.; Bulte, J.W.M.; Development of Zinc-Specific iCEST MRI as an Imaging Biomarker for Prostate Cancer. Angew. Chem. Int. Ed. Engl. 2019, 58, 15512–15517, 10.1002/anie.201909429.
  13. Ghosh, S.K.; Kim, P.; Zhang, X.A.; Yun, S.H.; Moore, A.; Lippard, S.J.; Medarova, Z.; A novel imaging approach for early detection of prostate cancer based on endogenous zinc sensing. Cancer Res. 2010, 70, 6119–6127, 10.1158/0008-5472.Can-10-1008.
  14. Zaichick, V.; Sviridova, T.V.; Zaichick, S.V.; Zinc in the human prostate gland: Normal, hyperplastic and cancerous. Int. Urol. Nephrol. 1997, 29, 565–574, 10.1007/bf02552202.
  15. Costello, L.C.; Franklin, R.B.; Prostatic fluid electrolyte composition for the screening of prostate cancer: A potential solution to a major problem. Prostate Cancer Prostatic Dis. 2009, 12, 17–24, 10.1038/pcan.2008.19.
  16. Cortesi, M.; Chechik, R.; Breskin, A.; Vartsky, D.; Ramon, J.; Raviv, G.; Volkov, A.; Fridman, E.; Evaluating the cancer detection and grading potential of prostatic-zinc imaging: A simulation study. Phys. Med. Biol. 2009, 54, 781–796, 10.1088/0031-9155/54/3/020.
  17. Clavijo Jordan, M.V.; Lo, S.T.; Chen, S.; Preihs, C.; Chirayil, S.; Zhang, S.; Kapur, P.; Li, W.H.; De Leon-Rodriguez, L.M.; Lubag, A.J.; et al.et al. Zinc-sensitive MRI contrast agent detects di erential release of Zn(II) ions from the healthy vs. malignant mouse prostate. Proc. Natl. Acad. Sci. USA 2016, 113, E5464–E5471, 10.1073/pnas.1609450113.
  18. Ma, Q.; Lin, Z.H.; Yang, N.; Li, Y.; Su, X.G.; A novel carboxymethyl chitosan-quantum dot-based intracellular probe for Zn2+ ion sensing in prostate cancer cells. Acta Biomater. 2014, 10, 868–874, 10.1016/j.actbio.2013.10.039.
  19. Fu, S.; Wan, X.; Du, C.; Wang, H.; Zhou, J.; Wang, Z.; A novel fluorescent probe for the early detection of prostate cancer based on endogenous zinc sensing. Prostate 2019, 79, 1378–1385, 10.1002/pros.23844.
  20. Zhang, X.A.; Hayes, D.; Smith, S.J.; Friedle, S.; Lippard, S.J.; New strategy for quantifying biological zinc by a modified zinpyr fluorescence sensor. J. Am. Chem. Soc. 2008, 130, 15788–15789, 10.1021/ja807156b.
  21. Franklin, R.B.; Feng, P.; Milon, B.; Desouki, M.M.; Singh, K.K.; Kajdacsy-Balla, A.; Bagasra, O.; Costello, L.C.; hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol. Cancer 2005, 4, 32, 16153295.
  22. Desouki, M.M.; Geradts, J.; Milon, B.; Franklin, R.B.; Costello, L.C.; hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol. Cancer 2007, 6, 37, 10.1186/1476-4598-6-37.
  23. Chen, Q.G.; Zhang, Z.; Yang, Q.; Shan, G.Y.; Yu, X.Y.; Kong, C.Z.; The role of zinc transporter ZIP4 in prostate carcinoma. Urol. Oncol. 2012, 30, 906–911, 10.1016/j.urolonc.2010.11.010.
  24. Robert, C.; Ribas, A.; Schachter, J.; Arance, A.; Grob, J.J.; Mortier, L.; Daud, A.; Carlino, M.S.; McNeil, C.M.; Lotem, M.; et al.et al. Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): Post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncol. 2019, 20, 1239–1251, 10.1016/s1470-2045(19)30388-2.
  25. Zhang, H.; Christensen, C.L.; Dries, R.; Oser, M.G.; Deng, J.; Diskin, B.; Li, F.; Pan, Y.; Zhang, X.; Yin, Y.; et al.et al. CDK7 Inhibition Potentiates Genome Instability Triggering Anti-Tumor Immunity in Small Cell Lung Cancer. Cancer Cell 2020, 37, 37–54, 10.1016/j.ccell.2019.11.003.
  26. Goldberg, M.S.; Improving cancer immunotherapy through nanotechnology. Nat. Rev. Cancer 2019, 19, 587–602, 10.1038/s41568-019-0186-9.
  27. Bryant, G.; Wang, L.; Mulholland, D.J.; Overcoming Oncogenic Mediated Tumor Immunity in Prostate Cancer. Int. J. Mol. Sci. 2017, 18, 1542, 10.3390/ijms18071542.
  28. Read, S.A.; Obeid, S.; Ahlenstiel, C.; Ahlenstiel, G.; The Role of Zinc in Antiviral Immunity. Adv. Nutr. 2019, 10, 696–710, 10.1093/advances/nmz013.
  29. Shankar, A.H.; Prasad, A.S.; Zinc and immune function: The biological basis of altered resistance to infection. Am. J. Clin. Nutr. 1998, 68, 447s–463s, 10.1093/ajcn/68.2.447S.
  30. Read, S.A.; O’Connor, K.S.; Suppiah, V.; Ahlenstiel, C.L.E.; Obeid, S.; Cook, K.M.; Cunningham, A.; Douglas, M.W.; Hogg, P.J.; Booth, D.; et al.et al. Zinc is a potent and specific inhibitor of IFN-lambda3 signalling. Nat. Commun. 2017, 8, 15245, 10.1038/ncomms15245.
  31. Prasad, A.S.; Bao, B.; Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications. Antioxidants 2019, 8, 164, 10.3390/antiox8060164.
  32. Mezzaroba, L.; Alfieri, D.F.; Colado Simao, A.N.; Vissoci Reiche, E.M.; The role of zinc, copper, manganese and iron in neurodegenerative diseases. Neurotoxicology 2019, 74, 230–241, 10.1016/j.neuro.2019.07.007.
  33. Miyai, T.; Hojyo, S.; Ikawa, T.; Kawamura, M.; Irie, T.; Ogura, H.; Hijikata, A.; Bin, B.H.; Yasuda, T.; Kitamura, H.; et al.et al. Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development. Proc. Natl. Acad. Sci. USA 2014, 111, 11780–11785, 10.1073/pnas.1323549111.
  34. Kitamura, H.; Morikawa, H.; Kamon, H.; Iguchi, M.; Hojyo, S.; Fukada, T.; Yamashita, S.; Kaisho, T.; Akira, S.; Murakami, M.; et al.et al. Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat. Immunol. 2006, 7, 971–977, 10.1038/ni1373.
  35. Yu, M.; Lee, W.W.; Tomar, D.; Pryshchep, S.; Czesnikiewicz-Guzik, M.; Lamar, D.L.; Li, G.; Singh, K.; Tian, L.; Weyand, C.M.; et al.et al. Regulation of T cell receptor signaling by activation-induced zinc influx. J. Exp. Med. 2011, 208, 775–785, 10.1084/jem.20100031.
  36. Anzilotti, C.; Swan, D.J.; Boisson, B.; Deobagkar-Lele, M.; Oliveira, C.; Chabosseau, P.; Engelhardt, K.R.; Xu, X.; Chen, R.; Alvarez, L.; et al.et al. An essential role for the Zn(2+) transporter ZIP7 in B cell development. Nat. Immunol. 2019, 20, 350–361, 10.1038/s41590-018-0295-8.
  37. Hojyo, S.; Miyai, T.; Fujishiro, H.; Kawamura, M.; Yasuda, T.; Hijikata, A.; Bin, B.H.; Irie, T.; Tanaka, J.; Atsumi, T.; et al.et al. Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength. Proc. Natl. Acad. Sci. USA 2014, 111, 11786–11791, 10.1073/pnas.1323557111.
  38. Sanna, A.; Firinu, D.; Zavattari, P.; Valera, P.; Zinc Status and Autoimmunity: A Systematic Review and Meta-Analysis. Nutrients 2018, 10, 68, 10.3390/nu10010068.
  39. Rosenkranz, E.; Hilgers, R.D.; Uciechowski, P.; Petersen, A.; Plumakers, B.; Rink, L.; Zinc enhances the number of regulatory T cells in allergen-stimulated cells from atopic subjects. Eur. J. Nutr. 2017, 56, 557–567, 10.1007/s00394-015-1100-1.
  40. Barnett, J.B.; Dao, M.C.; Hamer, D.H.; Kandel, R.; Brandeis, G.; Wu, D.; Dallal, G.E.; Jacques, P.F.; Schreiber, R.; Kong, E.; et al.et al. E ect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: A randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr. 2016, 103, 942–951, 10.3945/ajcn.115.115188.
  41. Prasad, A.S.; Kucuk, O.; Zinc in cancer prevention. Cancer Metastasis Rev. 2002, 21, 291–295, 10.1023/a:1021215111729.
  42. Miyahira, A.K.; Sharp, A.; Ellis, L.; Jones, J.; Kaochar, S.; Larman, H.B.; Quigley, D.A.; Ye, H.; Simons, J.W.; Pienta, K.J.; et al.et al. Prostate cancer research: The next generation; report from the 2019 Co ey-Holden Prostate Cancer Academy Meeting. Prostate 2020, 80, 113–132, 10.1002/pros.23934.
  43. Yunger, S.; Bar El, A.; Zeltzer, L.A.; Fridman, E.; Raviv, G.; Laufer, M.; Schachter, J.; Markel, G.; Itzhaki, O.; Besser, M.J.; et al. Tumor-infiltrating lymphocytes from human prostate tumors reveal anti-tumor reactivity and potential for adoptive cell therapy. Oncoimmunology 2019, 8, e1672494, 10.1080/2162402x.2019.1672494.
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Subjects: Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Dangdang Li
,
Daniel B. Stovall
,
Wenmeng Wang
,
Guangchao Sui
,
Mohammed Amine
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Revisions: 4 times (View History)
Update Date: 05 Nov 2021
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