Investigations into the Signaling Pathways Involving Glucose-Stimulated Zinc Secretion (GSZS) from Prostate Epithelial Cells In Vitro and In Vivo

Overview

Journal Mol Imaging Biol

Publisher Springer

Specialties Molecular Biology
Radiology

Date 2023 Apr 25

PMID 37097498

Authors

Daniel Parrott

Eul Hyun Suh

Pooyan Khalighinejad

Veronica Clavijo Jordan

Ivan Arreola

Su-Tang Lo

A Dean Sherry

Affiliations

Soon will be listed here.

Abstract

Purpose: Recently, we reported that exposure of prostate cells in vitro or the in vivo prostate to high glucose results in release of Zn ions, a process now referred to as glucose-stimulated zinc secretion (GSZS). To our knowledge, the metabolic event(s) that trigger GSZS remain largely unknown. Here, we explore several signaling pathways both in vitro using a prostate epithelial cell line and in vivo from the rat prostate.

Methods: PNT1A cells grown to confluence were washed and tagged with ZIMIR to monitor zinc secretion by optical methods. The expression levels of GLUT1, GLUT4, and Akt in cells cultured in either zinc-rich or zinc-poor media and after exposure to high versus low glucose were determined. Zinc secretion from the rat prostate in vivo as detected by MRI was compared in control animals after injection of glucose, deoxyglucose, or pyruvate to initiate zinc secretion and in animals pre-treated with WZB-117 (a GLUT1 inhibitor) or S961 (a peripheral insulin receptor inhibitor).

Results: PNT1A cells exposed to high levels of glucose secrete zinc whereas cells exposed to an equivalent amount of deoxyglucose or pyruvate do not. Expression of Akt was dramatically altered by zinc supplementation of the culture media but not after exposure to glucose while GLUT1 and GLUT4 levels were less affected. Rats pre-treated with WZB-117 prior to imaging showed a reduction in GSZS from the prostate compared to controls whereas rats pre-treated with S961 showed no difference. Interestingly, in comparison to PNT1A cells, pyruvate and deoxyglucose also stimulate zinc secretion in vivo likely through indirect mechanisms.

Conclusions: GSZS requires metabolism of glucose both in vitro (PNT1A cells) and in vivo (rat prostate). Pyruvate also stimulates zinc secretion in vivo but likely via an indirect pathway involving rapid production of glucose via gluconeogenesis. These combined results support the conclusion that glycolytic flux is required to trigger GSZS in vivo.

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References

Costello L, Franklin R . A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer. Arch Biochem Biophys. 2016; 611:100-112. PMC: 5083243. DOI: 10.1016/j.abb.2016.04.014. View

Costello L, Franklin R . The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer. 2006; 5:17. PMC: 1481516. DOI: 10.1186/1476-4598-5-17. View

Egan K . The Epidemiology of Benign Prostatic Hyperplasia Associated with Lower Urinary Tract Symptoms: Prevalence and Incident Rates. Urol Clin North Am. 2016; 43(3):289-97. DOI: 10.1016/j.ucl.2016.04.001. View

Aaron L, Franco O, Hayward S . Review of Prostate Anatomy and Embryology and the Etiology of Benign Prostatic Hyperplasia. Urol Clin North Am. 2016; 43(3):279-88. PMC: 4968575. DOI: 10.1016/j.ucl.2016.04.012. View

Gacci M, Corona G, Vignozzi L, Salvi M, Serni S, De Nunzio C . Metabolic syndrome and benign prostatic enlargement: a systematic review and meta-analysis. BJU Int. 2014; 115(1):24-31. DOI: 10.1111/bju.12728. View

Gacci M, Sebastianelli A, Salvi M, De Nunzio C, Vignozzi L, Corona G . Benign prostatic enlargement can be influenced by metabolic profile: results of a multicenter prospective study. BMC Urol. 2017; 17(1):22. PMC: 5379726. DOI: 10.1186/s12894-017-0211-9. View

Sebastianelli A, Gacci M . Current Status of the Relationship Between Metabolic Syndrome and Lower Urinary Tract Symptoms. Eur Urol Focus. 2018; 4(1):25-27. DOI: 10.1016/j.euf.2018.03.007. View

Vignozzi L, Rastrelli G, Corona G, Gacci M, Forti G, Maggi M . Benign prostatic hyperplasia: a new metabolic disease?. J Endocrinol Invest. 2014; 37(4):313-22. DOI: 10.1007/s40618-014-0051-3. View

Lo S, Parrott D, Jordan M, Joseph D, Strand D, Lo U . The Roles of ZnT1 and ZnT4 in Glucose-Stimulated Zinc Secretion in Prostate Epithelial Cells. Mol Imaging Biol. 2020; 23(2):230-240. PMC: 7914160. DOI: 10.1007/s11307-020-01557-x. View

10.

Li D, Chen S, Bellomo E, Tarasov A, Kaut C, Rutter G . Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR). Proc Natl Acad Sci U S A. 2011; 108(52):21063-8. PMC: 3248484. DOI: 10.1073/pnas.1109773109. View

11.

Liu Y, Zhang W, Cao Y, Liu Y, Bergmeier S, Chen X . Small compound inhibitors of basal glucose transport inhibit cell proliferation and induce apoptosis in cancer cells via glucose-deprivation-like mechanisms. Cancer Lett. 2010; 298(2):176-85. DOI: 10.1016/j.canlet.2010.07.002. View

12.

Liu Y, Cao Y, Zhang W, Bergmeier S, Qian Y, Akbar H . A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther. 2012; 11(8):1672-82. DOI: 10.1158/1535-7163.MCT-12-0131. View

13.

Vikram A, Jena G . S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats. Biochem Biophys Res Commun. 2010; 398(2):260-5. DOI: 10.1016/j.bbrc.2010.06.070. View

14.

Sharma P, Kumar S . S961, a biosynthetic insulin receptor antagonist, downregulates insulin receptor expression & suppresses the growth of breast cancer cells. Indian J Med Res. 2018; 147(6):545-551. PMC: 6118145. DOI: 10.4103/ijmr.IJMR_403_17. View

15.

Ginja M, Pires M, Gonzalo-Orden J, Seixas F, Correia-Cardoso M, Ferreira R . Anatomy and Imaging of Rat Prostate: Practical Monitoring in Experimental Cancer-Induced Protocols. Diagnostics (Basel). 2019; 9(3). PMC: 6787576. DOI: 10.3390/diagnostics9030068. View

16.

Rutter G, Chabosseau P, Bellomo E, Maret W, Mitchell R, Hodson D . Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?. Proc Nutr Soc. 2015; 75(1):61-72. DOI: 10.1017/S0029665115003237. View

17.

Zhang D, Li J, Wang F, Hu J, Wang S, Sun Y . 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett. 2014; 355(2):176-83. DOI: 10.1016/j.canlet.2014.09.003. View

18.

Halestrap A, Wilson M . The monocarboxylate transporter family--role and regulation. IUBMB Life. 2011; 64(2):109-19. DOI: 10.1002/iub.572. View

19.

Fukushima M, Lee S, Moro N, Hovda D, Sutton R . Metabolic and histologic effects of sodium pyruvate treatment in the rat after cortical contusion injury. J Neurotrauma. 2009; 26(7):1095-110. PMC: 2848946. DOI: 10.1089/neu.2008.0771. View

20.

Adeva-Andany M, Perez-Felpete N, Fernandez-Fernandez C, Donapetry-Garcia C, Pazos-Garcia C . Liver glucose metabolism in humans. Biosci Rep. 2016; 36(6). PMC: 5293555. DOI: 10.1042/BSR20160385. View