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ISRN Oncology  2013 

Endocytic Adaptor Protein Epsin Is Elevated in Prostate Cancer and Required for Cancer Progression

DOI: 10.1155/2013/420597

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Abstract:

Epsins have an important role in mediating clathrin-mediated endocytosis of ubiquitinated cell surface receptors. The potential role for epsins in tumorigenesis and cancer metastasis by regulating intracellular signaling pathways has largely not been explored. Epsins are reportedly upregulated in several types of cancer including human skin, lung, and canine mammary cancers. However, whether their expression is elevated in prostate cancer is unknown. In this study, we investigated the potential role of epsins in prostate tumorigenesis using the wild type or epsin-deficient human prostate cancer cells, LNCaP, in a human xenograft model, and the spontaneous TRAMP mouse model in wild type or epsin-deficient background. Here, we reported that the expression of epsins 1 and 2 is upregulated in both human and mouse prostate cancer cells and cancerous tissues. Consistent with upregulation of epsins in prostate tumors, we discovered that depletion of epsins impaired tumor growth in both the human LNCaP xenograft and the TRAMP mouse prostate. Furthermore, epsin depletion significantly prolonged survival in the TRAMP mouse model. In summary, our findings suggest that epsins may act as oncogenic proteins to promote prostate tumorigenesis and that depletion or inhibition of epsins may provide a novel therapeutic target for future prostate cancer therapies. 1. Introduction Solid tumors, such as those in prostate cancer, contribute the majority of all cancers and result in significant distant tumor metastasis to vital organs such as the lungs, brain, and bones [1, 2]. Prostate cancer contributes significantly to the morbidity and mortality of men in the United States [3]. Advanced prostate cancer is associated with significant mortality because the cancer metastasizes and spreads throughout the body, making recovery nearly impossible [1, 4]. The high rates of prostate cancer metastasis are, in part, caused by aggressive primary tumor growth in prostate [5]. Prostate tumorigenesis is a result of several upregulated signaling pathways, including Notch, EGF, FGF, and Wnt signaling, which promote tumor cell proliferation [6–11]. Understanding the mechanisms responsible for upregulated signaling during early tumorigenesis is an important step in identifying key regulators and potential therapeutic targets. More importantly, targeting early stages of tumorigenesis will facilitate stabilization of rapid growing tumors, leading to effective surgical removal of primary tumors and inhibition of further tumor metastasis. Epsins are endocytic adaptor proteins that regulate

References

[1]  Y. Jung, Y. Shiozawa, J. Wang et al., “Prevalence of prostate cancer metastases after intravenous inoculation provides clues into the molecular basis of dormancy in the bone marrow microenvironment,” Neoplasia, vol. 14, no. 5, pp. 429–439, 2012.
[2]  Y. Chen and H. I. Scher, “Prostate cancer in 2011: hitting old targets better and identifying new targets,” Nature Reviews Clinical Oncology, vol. 9, no. 2, pp. 70–72, 2012.
[3]  R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2012,” CA Cancer Journal for Clinicians, vol. 62, no. 1, pp. 10–29, 2012.
[4]  Z. I. Khamis, K. A. Iczkowski, and Q. X. A. Sang, “Metastasis suppressors in human benign prostate, intraepithelial neoplasia, and invasive cancer: their prospects as therapeutic agents,” Medicinal Research Reviews, vol. 32, no. 5, pp. 1026–1077, 2011.
[5]  S. Ramaswamy, K. N. Ross, E. S. Lander, and T. R. Golub, “A molecular signature of metastasis in primary solid tumors,” Nature Genetics, vol. 33, no. 1, pp. 49–54, 2003.
[6]  Z. Wang, Y. Li, S. Banerjee et al., “Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-κB signaling pathways,” Journal of Cellular Biochemistry, vol. 109, no. 4, pp. 726–736, 2010.
[7]  J. K. Oosterhoff, J. A. Grootegoed, and L. J. Blok, “Expression profiling of androgen-dependent and -independent LNCaP cells: EGF versus androgen signalling,” Endocrine-Related Cancer, vol. 12, no. 1, pp. 135–148, 2005.
[8]  J. K. Oosterhoff, L. C. Kühne, J. A. Grootegoed, and L. J. Blok, “EGF signalling in prostate cancer cell lines is inhibited by a high expression level of the endocytosis protein REPS2,” International Journal of Cancer, vol. 113, no. 4, pp. 561–567, 2005.
[9]  J. Wang, W. Yu, Y. Cai, C. Ren, and M. M. Ittmann, “Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression,” Neoplasia, vol. 10, no. 8, pp. 847–856, 2008.
[10]  S. Gupta, K. Iljin, H. Sara et al., “FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells,” Cancer Research, vol. 70, no. 17, pp. 6735–6745, 2010.
[11]  K. G. Bache, T. Slagsvold, and H. Stenmark, “Defective downregulation of receptor tyrosine kinases in cancer,” EMBO Journal, vol. 23, no. 14, pp. 2707–2712, 2004.
[12]  H. Barriere, C. Nemes, D. Lechardeur, M. Khan-Mohammad, K. Fruh, and G. L. Lukacs, “Molecular basis of oligoubiquitin-dependent internalization of membrane proteins in mammalian cells,” Traffic, vol. 7, no. 3, pp. 282–297, 2006.
[13]  H. Chen and P. De Camilli, “The association of epsin with ubiquitinated cargo along the endocytic pathway is negatively regulated by its interaction with clathrin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 8, pp. 2766–2771, 2005.
[14]  H. Chen, S. Fre, V. I. Slepnev et al., “Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis,” Nature, vol. 394, no. 6695, pp. 793–797, 1998.
[15]  M. G. J. Ford, I. G. Mills, B. J. Peter et al., “Curvature of clathrin-coated pits driven by epsin,” Nature, vol. 419, no. 6905, pp. 361–366, 2002.
[16]  M. J. Hawryluk, P. A. Keyel, S. K. Mishra, S. C. Watkins, J. E. Heuser, and L. M. Traub, “Epsin 1 is a polyubiquitin-selective clathrin-associated sorting protein,” Traffic, vol. 7, no. 3, pp. 262–281, 2006.
[17]  J. A. Rosenthal, H. Chen, V. I. Slepnev et al., “The epsins define a family of proteins that interact with components of the clathrin coat and contain a new protein module,” Journal of Biological Chemistry, vol. 274, no. 48, pp. 33959–33965, 1999.
[18]  S. C. Shih, D. J. Katzmann, J. D. Schnell, M. Sutanto, S. D. Emr, and L. Hicke, “Epsins and Vps27p/Hrs contain ubiquitin-binding domains that function in receptor endocytosis,” Nature Cell Biology, vol. 4, no. 5, pp. 389–393, 2002.
[19]  S. Sugiyama, S. Kishida, K. Chayama, S. Koyama, and A. Kikuchi, “Ubiquitin-interacting motifs of epsin are involved in the regulation of insulin-dependent endocytosis,” Journal of Biochemistry, vol. 137, no. 3, pp. 355–364, 2005.
[20]  B. Wendland, “Epsins: adaptors in endocytosis?” Nature Reviews Molecular Cell Biology, vol. 3, no. 12, pp. 971–977, 2002.
[21]  G. Ko, S. Paradise, H. Chen et al., “Selective high-level expression of epsin 3 in gastric parietal cells, where it is localized at endocytic sites of apical canaliculi,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 50, pp. 21511–21516, 2010.
[22]  H. Chen, G. Ko, A. Zatti et al., “Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 33, pp. 13838–13843, 2009.
[23]  S. Pasula, X. Cai, Y. Dong et al., “Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling,” Journal of Clinical Investigation, vol. 122, no. 12, pp. 4424–4438, 2012.
[24]  R. S. Kerbel, “Tumor angiogenesis,” New England Journal of Medicine, vol. 358, no. 19, pp. 2039–2049, 2008.
[25]  B. G. Coon, J. Burgner, J. H. Camonis, and R. C. Aguilar, “The Epsin family of endocytic adaptors promotes fibrosarcoma migration and invasion,” Journal of Biological Chemistry, vol. 285, no. 43, pp. 33073–33081, 2010.
[26]  B. G. Coon, D. M. DiRenzo, S. F. Konieczny, and R. C. Aguilar, “Epsins' novel role in cancer cell invasion,” Communicative & Integrative Biology, vol. 4, no. 1, pp. 95–97, 2011.
[27]  D. Mukherjee, B. G. Coon, D. F. Edwards et al., “The yeast endocytic protein Epsin 2 functions in a cell-division signaling pathway,” Journal of Cell Science, vol. 122, no. 14, pp. 2453–2463, 2009.
[28]  B. Tanos and E. Rodriguez-Boulan, “The epithelial polarity program: machineries involved and their hijacking by cancer,” Oncogene, vol. 27, no. 55, pp. 6939–6957, 2008.
[29]  C. Rossé, S. L'Hoste, N. Offner, A. Picard, and J. Camonis, “RLIP, an effector of the Ral GTPases, is a platform for Cdk1 to phosphorylate Epsin during the switch off of endocytosis in mitosis,” Journal of Biological Chemistry, vol. 278, no. 33, pp. 30597–30604, 2003.
[30]  R. C. Aguilar, S. A. Longhi, J. D. Shaw et al., “Epsin N-terminal homology domains perform an essential function regulating Cdc42 through binding Cdc42 GTPase-activating proteins,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 11, pp. 4116–4121, 2006.
[31]  N. M. Mollberg, G. Steinert, M. Aigner et al., “Overexpression of RalBP1 in colorectal cancer is an independent predictor of poor survival and early tumor relapse,” Cancer Biology and Therapy, vol. 13, no. 8, pp. 695–701, 2012.
[32]  J. S. Horoszewicz, S. S. Leong, and E. Kawinski, “LNCaP model of human prostatic carcinoma,” Cancer Research, vol. 43, no. 4, pp. 1809–1818, 1983.
[33]  N. M. Greenberg, F. DeMayo, D. Medina et al., “Prostate cancer in a transgenic mouse,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 8, pp. 3439–3443, 1995.
[34]  J. R. Gingrich, R. J. Barrios, M. W. Kattan, H. S. Nahm, M. J. Finegold, and N. M. Greenberg, “Androgen-independent prostate cancer progression in the TRAMP model,” Cancer Research, vol. 57, no. 21, pp. 4687–4691, 1997.
[35]  J. R. Gingrich, R. J. Barrios, R. A. Morton et al., “Metastatic prostate cancer in a transgenic mouse,” Cancer Research, vol. 56, no. 18, pp. 4096–4102, 1996.
[36]  J. R. Gingrich and N. M. Greenberg, “A transgenic mouse prostate cancer model,” Toxicologic Pathology, vol. 24, no. 4, pp. 502–504, 1996.
[37]  G. N. Thalmann, P. E. Anezinis, S. M. Chang et al., “Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer,” Cancer Research, vol. 54, no. 10, pp. 2577–2581, 1994.
[38]  H. C. Wu, J. T. Hsieh, M. E. Gleave, N. M. Brown, S. Pathak, and L. W. K. Chung, “Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells,” International Journal of Cancer, vol. 57, no. 3, pp. 406–412, 1994.
[39]  J. R. Gingrich, R. J. Barrios, B. A. Foster, and N. M. Greenberg, “Pathologic progression of autochthonous prostate cancer in the TRAMP model,” Prostate Cancer and Prostatic Diseases, vol. 2, no. 2, pp. 70–75, 1999.

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