11. Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, et al. (2002) Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 8: 1168–1171. 12. Edwards J, Krishna NS, Witton CJ, Bartlett JM (2003) Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin Cancer Res 9: 5271–5281. 13. Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, et al. (2004) Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res 64: 5232–5236. 14. McCall P, Gemmell LK, Mukherjee R, Bartlett JM, Edwards J (2008) Phosphorylation of the androgen receptor is associated with reduced survival in hormone-refractory prostate cancer patients. Br J Cancer 98: 1094–1101. 15. Abrahamsson PA (1999) Neuroendocrine cells in tumour growth of the prostate. Endocr Relat Cancer 6: 503–519. 16. Ito T, Yamamoto S, Ohno Y, Namiki K, Aizawa T, et al. (2001) Up-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence. Oncol Rep 8: 1221–1224. 17. Ismail AH, Landry F, Aprikian AG, Chevalier S (2002) Androgen ablation promotes neuroendocrine cell differentiation in dog and human prostate. Prostate 51: 117–125. 18. Kamiya N, Akakura K, Suzuki H, Isshiki S, Komiya A, et al. (2003) Pretreatment serum level of neuron specific enolase (NSE) as a prognostic factor in metastatic prostate cancer patients treated with endocrine therapy. Eur Urol 44: 309–314; discussion. 19. Hirano D, Okada Y, Minei S, Takimoto Y, Nemoto N (2004) Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol 45: 586–592; discussion. 20. Shen R, Dorai T, Szaboles M, Katz AE, Olsson CA, et al. (1997) Transdifferentiation of Cultured Human Prostate Cancer Cells to a Neuroen- docrine Cell Phenotype in a Hormone-Depleted Medium Urol Oncol 3: 67–75. 21. Burchardt T, Burchardt M, Chen MW, Cao Y, de la Taille A, et al. (1999) Transdifferentiation of prostate cancer cells to a neuroendocrine cell phenotype in vitro and in vivo. J Urol 162: 1800–1805. 22. Jongsma J, Oomen MH, Noordzij MA, Van Weerden WM, Martens GJ, et al. (2000) Androgen deprivation of the PC-310 human prostate cancer model system induces neuroendocrine differentiation. Cancer Res 60: 741–748. 23. Zhang XQ, Kondrikov D, Yuan TC, Lin FF, Hansen J, et al. (2003) Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion- induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene 22: 6704–6716. 24. Wu C, Zhang L, Bourne PA, Reeder JE, di Sant’Agnese PA, et al. (2006) Protein tyrosine phosphatase PTP1B is involved in neuroendocrine differentiation of prostate cancer. Prostate 66: 1125–1135. 25. Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, et al. (2003) Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 55: 219–237. 26. Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4: 397–407. 27. Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, et al. (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1- phosphate. Nature 381: 800–803. 28. Xia P, Gamble JR, Wang L, Pitson SM, Moretti PA, et al. (2000) An oncogenic role of sphingosine kinase. Curr Biol 10: 1527–1530. 29. French KJ, Schrecengost RS, Lee BD, Zhuang Y, Smith SN, et al. (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63: 5962–5969. 30. Van Brocklyn JR, Jackson CA, Pearl DK, Kotur MS, Snyder PJ, et al. (2005) Sphingosine kinase-1 expression correlates with poor survival of patients with glioblastoma multiforme: roles of sphingosine kinase isoforms in growth of glioblastoma cell lines. J Neuropathol Exp Neurol 64: 695–705. 31. Johnson KR, Johnson KY, Crellin HG, Ogretmen B, Boylan AM, et al. (2005) Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem 53: 1159–1166. 32. Sobue S, Iwasaki T, Sugisaki C, Nagata K, Kikuchi R, et al. (2006) Quantitative RT-PCR analysis of sphingolipid metabolic enzymes in acute leukemia and myelodysplastic syndromes. Leukemia 20: 2042–2046. 33. Kawamori T, Osta W, Johnson KR, Pettus BJ, Bielawski J, et al. (2006) Sphingosine kinase 1 is up-regulated in colon carcinogenesis. Faseb J 20: 386–388. SphK1 and Androgen Signaling 34. Ruckhaberle E, Rody A, Engels K, Gaetje R, von Minckwitz G, et al. (2008) Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer. Breast Cancer Res Treat 112: 41–52. 35. Nava VE, Cuvillier O, Edsall LC, Kimura K, Milstien S, et al. (2000) Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells. Cancer Res 60: 4468–4474. 36. Pchejetski D, Golzio M, Bonhoure E, Calvet C, Doumerc N, et al. (2005) Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res 65: 11667–11675. 37. Pchejetski D, Doumerc N, Golzio M, Naymark M, Teissie J, et al. (2008) Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models. Mol Cancer Ther 7: 1836–1845. 38. Sauer L, Nunes J, Salunkhe V, Skalska L, Kohama T, et al. (2009) Sphingosine kinase 1 inhibition sensitizes hormone-resistant prostate cancer to docetaxel. Int J Cancer 125: 2728–2736. 39. Sun M, Yang L, Feldman RI, Sun XM, Bhalla KN, et al. (2003) Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and Src. J Biol Chem 278: 42992–43000. 40. Baron S, Manin M, Beaudoin C, Leotoing L, Communal Y, et al. (2004) Androgen receptor mediates non-genomic activation of phosphatidylinositol 3- OH kinase in androgen-sensitive epithelial cells. J Biol Chem 279: 14579–14586. 41. Cox ME, Deeble PD, Lakhani S, Parsons SJ (1999) Acquisition of neuroendocrine characteristics by prostate tumor cells is reversible: implications for prostate cancer progression. Cancer Res 59: 3821–3830. 42. Zelivianski S, Verni M, Moore C, Kondrikov D, Taylor R, et al. (2001) Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta 1539: 28–43. 43. Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, et al. (2005) A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res 65: 5263–5271. 44. Bang YJ, Pirnia F, Fang WG, Kang WK, Sartor O, et al. (1994) Terminal neuroendocrine differentiation of human prostate carcinoma cells in response to increased intracellular cyclic AMP. Proc Natl Acad Sci U S A 91: 5330–5334. 45. Yuan TC, Veeramani S, Lin MF (2007) Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocr Relat Cancer 14: 531–547. 46. Goodin JL, Rutherford CL (2002) Identification of differentially expressed genes during cyclic adenosine monophosphate-induced neuroendocrine differentiation in the human prostatic adenocarcinoma cell line LNCaP. Mol Carcinog 33: 88–98. 47. Machwate M, Rodan SB, Rodan GA, Harada SI (1998) Sphingosine kinase mediates cyclic AMP suppression of apoptosis in rat periosteal cells. Mol Pharmacol 54: 70–77. 48. Eto M, Bennouna J, Hunter OC, Hershberger PA, Kanto T, et al. (2003) C16 ceramide accumulates following androgen ablation in LNCaP prostate cancer cells. Prostate 57: 66–79. 49. Taha TA, Kitatani K, Bielawski J, Cho W, Hannun YA, et al. (2005) Tumor necrosis factor induces the loss of sphingosine kinase-1 by a cathepsin B- dependent mechanism. J Biol Chem 280: 17196–17202. 50. Pchejetski D, Kunduzova O, Dayon A, Calise D, Seguelas MH, et al. (2007) Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis. Circ Res 100: 41–49. 51. Pitson SM, D’Andrea R J, Vandeleur L, Moretti PA, Xia P, et al. (2000) Human sphingosine kinase: purification, molecular cloning and characterization of the native and recombinant enzymes. Biochem J 350 Pt 2: 429–441. 52. Bonhoure E, Pchejetski D, Aouali N, Morjani H, Levade T, et al. (2006) Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting sphingosine kinase-1. Leukemia 20: 95–102. 53. Bonhoure E, Lauret A, Barnes DJ, Martin C, Malavaud B, et al. (2008) Sphingosine kinase-1 is a downstream regulator of imatinib-induced apoptosis in chronic myeloid leukemia cells. Leukemia 22: 971–979. 54. Cuvillier O, Levade T (2001) Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria. Blood 98: 2828–2836. 55. Olivera A, Kohama T, Edsall L, Nava V, Cuvillier O, et al. (1999) Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol 147: 545–558. PLoS ONE | www.plosone.org 13 November 2009 | Volume 4 | Issue 11 | e8048