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Intracellular Elemental Patterns of Apoptosis Resistance in Transdifferentiated Androgen-Dependent Prostatic Carcinoma Cells

Published online by Cambridge University Press:  04 August 2016

Mercedes Salido  and
Jose Vilches
Mercedes Salido*
Affiliation:
Department of Histology, Servicio Central de Investigacion Biomedica y en Ciencias de la Salud (SC-IBM), School of Medicine, University of Cadiz, c/Dr. Marañon, 3. 11002 Cádiz, Spain
Jose Vilches
Affiliation:
Department of Histology, Servicio Central de Investigacion Biomedica y en Ciencias de la Salud (SC-IBM), School of Medicine, University of Cadiz, c/Dr. Marañon, 3. 11002 Cádiz, Spain
*
*Corresponding author. mercedes.salido@uca.es
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Abstract

The acquisition of neuroendocrine (NE) characteristics by prostate cancer (PC) cells relates to tumor progression and hormone resistance. PC cells may survive and function in androgen-deprived environments, where they could establish paracrine signaling networks, providing stimuli for the propagation of local carcinoma cells. We previously demonstrated, using electron probe X-ray microanalysis (EPXMA), in LNCaP, PC-3, and Du 145 cell lines that apoptosis is associated with intracellular elemental changes, and that the NE secretory products, bombesin and calcitonin, inhibit etoposide-induced apoptosis, as well as some of these elemental changes. In this study, LNCaP cells were induced in vitro to transdifferentiate under androgen deprivation, to mimic the role of NE cells in the apoptotic activity of transdifferentiated androgen-dependent PC cells. Changes in intracellular ion content associated with apoptosis, assessed by EPXMA, demonstrate that the transdifferentiated LNCaP cells are resistant to etoposide-induced apoptosis and also to the etoposide-induced elemental changes. The aggressive malignant potential of PC with neuroendocrine differentiation, associated with hormonal independence, is partly because of the ability that most NE tumor cells have to escape apoptosis, which can enhance the malignant properties of tumor cells and may have therapeutic implications as tumor cells are usually resistant to cytotoxic drugs as etoposide.

Keywords

apoptosisneuroendocrinetransdifferentiationprostate carcinomaion changeselectron probe X-ray microanalysis
Type
Biological Applications
Information
Microscopy and Microanalysis , Volume 22 , Issue 4 , August 2016 , pp. 865 - 877
Copyright
© Microscopy Society of America 2016 

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References

Alberti, C. (2010). Neuroendocrine differentiation in prostate carcinoma: Focusing on its pathophysiologic mechanisms and pathological features. G Chir 31, 568–574.Google Scholar
Arrebola, F., Zabiti, S., Cañizares, F.J., Cubero, M.A., Crespo, P.V. & Fernández-Segura, E. (2005). Changes in intracellular sodium, chlorine, and potassium concentrations in staurosporine-induced apoptosis. J Cell Physiol 204, 500–507.Google Scholar
Berruti, A., Bollito, E., Cracco, C.M., Volante, M., Ciccone, G., Porpiglia, F., Papotti, M., Scarpa, R.M. & Dogliotti, L. (2010). The prognostic role of immunohistochemical chromogranin A expression in prostate cancer patients is significantly modified by androgen-deprivation therapy. Prostate 70, 718–726.CrossRefGoogle ScholarPubMed
Bortner, C.D., Hughes, F.M. Jr. & Cidlowski, J.A. (1997). A primary role for K+ and Na+ efflux in the activation of apoptosis. J Biol Chem 272, 32436–32442.Google Scholar
Chang, P.C., Wang, T.Y., Chang, Y.T., Chu, C.Y., Lee, C.L., Hsu, H.W., Zhou, T.A., Wu, Z., Kim, R.H., Desai, S.J., Liu, S. & Kung, H.J. (2014). Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. PLoS One 9(2), e88556.Google Scholar
Cindolo, L., Cantile, M., Vacherot, F., Terry, S. & Taille, A. (2007). Neuroendocrine differentiation in prostate cancer: From lab to bedside. Urol Int 79, 287–296.Google Scholar
Collins, C.C., Volik, S.V., Lapuk, A.V., Wang, Y., Gout, P.W., Wu, C., Xue, H., Cheng, H., Haegert, A., Bell, R.H., Brahmbhatt, S., Anderson, S., Fazli, L., Hurtado-Coll, A., Rubin, M.A., Demichelis, F., Beltran, H., Hirst, M., Marra, M., Maher, C.A., Chinnaiyan, A.M., Gleave, M., Bertino, J.R., Lubin, M. & Wang, Y. (2012). Next generation sequencing of prostate cancer from a patient identifies a deficiency of methylthioadenosine phosphorylase, an exploitable tumor target. Mol Cancer Ther 11, 775–783.Google Scholar
Conteduca, V., Aieta, M., Amadori, D. & De Giorgi, U. (2014). Neuroendocrine differentiation in prostate cancer, current and emerging therapy strategies. Crit Rev Oncol Hematol 92, 11–24.Google Scholar
Conteduca, V., Burgio, S.L., Menna, C., Carretta, E., Rossi, L., Bianchi, E., Masini, C., Amadori, D. & De Giorgi, U. (2014). Chromogranin A is a potential prognostic marker in prostate cancer patients treated with enzalutamide. Prostate 74, 1691–1696.Google Scholar
Dallaporta, B., Marchetti, P., De Pablo, M.A., Maisse, C., Duc, H.T., Metivier, D., Zamzami, N., Geuskens, M. & Kroemer, G. (1999). Plasma membrane potential in thymocyte apoptosis. J Immunol 162, 6534–6542.Google Scholar
DaSilva, J.O., Amorino, G.P., Casarez, E.V., Pemberton, B. & Parsons, S.J. (2013). Neuroendocrine-derived peptides promote prostate cancer cell survival through activation of IGF-1R signaling. Prostate 73, 801–812.Google Scholar
Fernandez-Segura, E., Canizares, F.J., Cubero, M.A., Warley, A. & Campos, A. (1999). Changes in elemental content during apoptotic death studied by electron probe X-ray microanalysis. Exp Cell Res 253, 454–462.CrossRefGoogle ScholarPubMed
Fléchon, A., Pouessel, D., Ferlay, C., Perol, D., Beuzeboc, P., Gravis, G., Joly, F., Oudard, S., Deplanque, G., Zanetta, S., Fargeot, P., Priou, F., Droz, J.P. & Culine, S. (2011). Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation, results of the French Genito-Urinary Tumor Group (GETUG) P01 trial. Ann Oncol 22, 2476–2481.Google Scholar
Frigo, D.E. & McDonnell, D.P. (2008). Differential effects of prostate cancer therapeutics on neuroendocrine transdifferentiation. Mol Cancer Ther 7, 659–669.Google Scholar
Glinicki, P. & Jeske, W. (2011). Chromogranin A (CgA)—The influence of various factors in vivo and in vitro, and existing disorders on its concentration in blood. Endokrynol Pol 62, 25–28.Google Scholar
Grigore, A.D., Ben-Jacob, E. & Farach-Carson, M.C. (2015). Prostate cancer and neuroendocrine differentiation, more neuronal, less endocrine? Front Oncol 5, 37.Google Scholar
Hu, C.D., Choo, R. & Huang, J. (2015). Neuroendocrine differentiation in prostate cancer, a mechanism of radioresistance and treatment failure. Front Oncol 5, 90.Google Scholar
Hughes, F.M., Jr. & Cidlowski, J.A. (1999). Potassium is a critical regulator of apoptotic enzymes in vitro and in vivo . Adv Enzyme Regul 39, 157–171.CrossRefGoogle ScholarPubMed
Krauss, D.J., Amin, M., Stone, B., Ye, H., Hayek, S., Cotant, M., Hafron, J. & Brabbins, D.S. (2014). Chromogranin A staining as a prognostic variable in newly diagnosed Gleason score 7–10 prostate cancer treated with definitive radiotherapy. Prostate 74, 520–527.CrossRefGoogle ScholarPubMed
Lapuk, A.V., Wu, C., Wyatt, A.W., Mcpherson, A., Mcconeghy, B.J., Brahmbhatt, S., Mo, F., Zoubeidi, A., Anderson, S., Bell, R.H., Haegert, A., Shukin, R., Wang, Y., Fazli, L., Hurtado-Coll, A., Jones, E.C., Hach, F., Hormozdiari, F., Hajirasouliha, I., Boutros, P.C., Bristow, R.G., Zhao, Y., Marra, M.A., Fanjul, A., Maher, C.A., Chinnaiyan, A.M., Rubin, M.A., Beltran, H., Sahinalp, S.C., Gleave, M.E., Volik, S.V. & Collins, C.C. (2012). From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancer. J Pathol 227, 286–297.Google Scholar
Matei, D.V., Renne, G., Pimentel, M., Sandri, M.T., Zorzino, L., Botteri, E., De Cicco, C., Musi, G., Brescia, A., Mazzoleni, F., Tringali, V., Detti, S. & De Cobelli, O. (2012). Neuroendocrine differentiation in castration-resistant prostate cancer, a systematic diagnostic attempt. Clin Genitourin Cancer 10, 164–173.CrossRefGoogle ScholarPubMed
Montague, J.W., Bortner, C.D., Hughes, F.M., Jr . & Cidlowski, J.A. (1999). A necessary role for reduced intracellular potassium during the DNA degradation phase of apoptosis. Steroids 64, 563–569.CrossRefGoogle ScholarPubMed
Nouri, M., Ratther, E., Stylianou, N., Nelson, C.C., Hollier, B.G. & Williams, E.D. (2014). Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer, an opportunity for intervention. Front Oncol 4, 370.CrossRefGoogle ScholarPubMed
Ramirez-Balderrama, L., Lopez-Briones, S., Daza-Benitez, L., Macias, M.H., Lopez-Gaytan, T. & Perez-Vazquez, V. (2013). Neuroendocrine differentiation in prostate adenocarcinome. Gac Med Mex 149, 639–645.Google Scholar
Ramos, J.M., Arrebola, F., Fernández-Cervilla, F.J., Crespo, V. & Fernández-Segura, E. (2011). Electron probe X-ray microanalysis of cisplatin-induced cell death in rat pheochromocytoma PC12 cells. Histol Histopathol 26, 333–342.Google ScholarPubMed
Roomans, G.M. (1988). Quantitative X-ray microanalysis of biological specimens. J Electron Microsc Tech 9, 19–44.Google Scholar
Roomans, G.M. (1991). X-ray microanalysis. In Biophysical Electron Microscopy, Hawkes, P.W. & Valdre, U. (Eds.), pp. 347–412. London: Academic Press.Google Scholar
Roomans, G.M. & Seveus, L.A. (1976). Subcellular localization of diffusible ions in the yeast Saccharomyces cerevisiae, quantitative microprobe analysis of thin freeze-dried sections. J Cell Sci 21, 119–127.Google Scholar
Sagnak, L., Topaloglu, H., Ozok, U. & Ersoy, H. (2011). Prognostic significance of neuroendocrine differentiation in prostate adenocarcinoma. Clin Genitourin Cancer 9, 73–80.Google Scholar
Salido, M., Gonzalez, J.L. & Vilches, J. (2007). Loss of mitochondrial membrane potential is inhibited by bombesin in etoposide-induced apoptosis in PC-3 prostate carcinoma cells. Mol Cancer Ther 6, 1292–1299.CrossRefGoogle ScholarPubMed
Salido, M., Vilches, J. & López, A. (2000). Neuropeptides bombesin and calcitonin induce resistance to etoposide induced apoptosis in prostate cancer cell lines. Histol Histopathol 15, 729–738.Google Scholar
Salido, M., Vilches, J., López, A. & Roomans, G.M. (2001). X-ray microanalysis of etoposide-induced apoptosis in the PC-3 prostatic cancer cell line. Cell Biol Int 25, 499–508.Google Scholar
Salido, M., Vilches, J., López, A. & Roomans, G.M. (2002). Neuropeptides bombesin and calcitonin inhibit apoptosis-related elemental changes in prostate carcinoma cell lines. Cancer 94, 368–377.Google Scholar
Salido, M., Vilches, J. & Roomans, G.M. (2004). Changes in elemental concentrations in LNCaP cells are associated with a protective effect of neuropeptides on etoposide-induced apoptosis. Cell Biol Int 28, 397–402.Google Scholar
Santoni, M., Conti, A., Burattini, L., Berardi, R., Scarpelli, M., Cheng, L., Lopez-Beltran., A., Cascinu, S. & Montironi, R. (2014). Neuroendocrine differentiation in prostate cancer: novel morphological insights and future therapeutic perspectives. Biochim Biophys Acta 1846, 630–637.Google Scholar
Sauer, C.G., Roemer, A. & Grobholz, R. (2006). Genetic analysis of neuroendocrine tumor cells in prostatic carcinoma. Prostate 66, 227–234.CrossRefGoogle ScholarPubMed
Sun, Y., Niu, J. & Huang, J. (2009). Neuroendocrine differentiation in prostate cancer. Am J Transl Res 1, 148–162.Google Scholar
Surcel, C.I., Van Oort, I.M., Sooriakumaran, P., Briganti, A., De Visschere, P.J.L., Fütterer, J.J., Ghadjar, P., Isbarn, H., Ost, P., Van Den Bergh, R.C., Yossepowitch, O., Giannarini, G. & Ploussard, G. (2014). Prognostic effect of neuroendocrine differentiation in prostate cancer, a critical review. Urol Oncol 16, 265.e1–265.e7.Google Scholar
Tagawa, S.T. (2014). Neuroendocrine prostate cancer after hormonal therapy, knowing is half the battle. J Clin Oncol 32, 3360–3364.Google Scholar
Tawadros, T., Alonso, F., Jichlinski, P., Clarke, N., Calandra, T., Haefliger, J.A. & Roger, T. (2013). Release of macrophage migration inhibitory factor by neuroendocrine-differentiated LNCaP cells sustains the proliferation and survival of prostate cancer cells. Endocr Relat Cancer 20, 137–149.Google Scholar
Terry, S. & Beltran, H. (2014). The many faces of neuroendocrine differentiation in prostate cancer progression. Front Oncol 4, 60.Google Scholar
Terry, S., Maillé, P., Baaddi, H., Kheuang, L., Soyeux, P., Nicolaiew, N., Ceraline, J., Firlej, V., Beltran, H., Allory, Y., De La Taille, A. & Vacherot, F. (2013). Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. Neoplasia 15, 761–772.Google Scholar
Tsapakidis, K., Vlachostergios, P.J., Voutsadakis, I.A., Befani, C.D., Patrikidou, A., Hatzidaki, E., Moutzouris, G., Liakos, P. & Papandreou, C.N. (2012). Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells. Int J Urol 19, 565–574.Google Scholar
Vilches, J., Salido, M., Fernández-Segura, E. & Roomans, G.M. (2004). Neuropeptides, apoptosis and ion changes in prostate cancer. Methods of study and recent developments. Histol Histopathol 19, 951–961.Google Scholar
Vlachostergios, P.J. & Papandreou, C.N. (2015). Targeting neuroendocrine prostate cancer, molecular and clinical perspectives. Front Oncol 5, 6.Google Scholar
Warley, A. (2016). Development and comparison of the methods for quantitative electron probe X-ray microanalysis analysis of thin specimens and their application to biological material. J Microsc 261, 177–184.Google Scholar
Zhang, C.H., Soori, M., Miles, F.L., Sikes, R.A., Carson, D.D., Chung, L.W.K. & Farach-Carson, M.C. (2011). Paracrine factors produced by bone marrow stromal cells induce apoptosis and neuroendocrine differentiation in prostate cancer cells. Prostate 71, 157–167.Google Scholar