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Cellular and Molecular Life Sciences

, Volume 75, Issue 5, pp 939–963 | Cite as

Protein kinase D inhibitor CRT0066101 suppresses bladder cancer growth in vitro and xenografts via blockade of the cell cycle at G2/M

  • Qingdi Quentin Li
  • Iawen Hsu
  • Thomas Sanford
  • Reema Railkar
  • Navin Balaji
  • Carole Sourbier
  • Cathy Vocke
  • K. C. Balaji
  • Piyush K. Agarwal
Original Article

Abstract

The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD2 silencing arrested bladder cancer cells at the G2/M phase, the arrest being accompanied by decreases in the levels of cyclin B1, CDK1 and phospho-CDK1 (Thr161) and increases in the levels of p27Kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity. These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression.

Keywords

G2/M cell cycle arrest Invasion and migration c-Jun phosphorylation Protein kinase D inhibitor RNA interference TCGA database 

Notes

Acknowledgements

This research was supported by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interests.

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefPubMedGoogle Scholar
  2. 2.
    Torre LA, Siegel RL, Ward EM, Jemal A (2016) Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomark Prev 25:16–27CrossRefGoogle Scholar
  3. 3.
    Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, Lotan Y (2017) Bladder cancer. Nat Rev Dis Prim 3:17022CrossRefPubMedGoogle Scholar
  4. 4.
    Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet 374:239–249CrossRefPubMedGoogle Scholar
  5. 5.
    Fletcher A, Choudhury A, Alam N (2011) Metastatic bladder cancer: a review of current management. ISRN Urol 2011:545241PubMedPubMedCentralGoogle Scholar
  6. 6.
    Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866CrossRefPubMedGoogle Scholar
  7. 7.
    Dovedi SJ, Davies BR (2009) Emerging targeted therapies for bladder cancer: a disease waiting for a drug. Cancer Metastasis Rev 28:355–367CrossRefPubMedGoogle Scholar
  8. 8.
    Bellmunt J, Petrylak DP (2012) New therapeutic challenges in advanced bladder cancer. Semin Oncol 39:598–607CrossRefPubMedGoogle Scholar
  9. 9.
    Weintraub MD, Li QQ, Agarwal PK (2014) Advances in intravesical therapy for the treatment of non-muscle invasive bladder cancer (review). Mol Clin Oncol 2:656–660CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Mohammed AA, El-Tanni H, El-Khatib HM, Mirza AA, Mirza AA, Alturaifi TH (2016) Urinary bladder cancer: biomarkers and target therapy, new era for more attention. Oncol Rev 10:320CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Alpsoy A, Gunduz U (2015) Protein kinase D2 silencing reduced motility of doxorubicin-resistant MCF7 cells. Tumour Biol 36:4417–4426CrossRefPubMedGoogle Scholar
  12. 12.
    Zhu Y, Cheng Y, Guo Y, Chen J, Chen F, Luo R, Li A (2016) Protein kinase D2 contributes to TNF-α-induced epithelial mesenchymal transition and invasion via the PI3 K/GSK-3β/β-catenin pathway in hepatocellular carcinoma. Oncotarget 7:5327–5341PubMedGoogle Scholar
  13. 13.
    Wong C, Jin ZG (2005) Protein kinase C-dependent protein kinase D activation modulates ERK signal pathway and endothelial cell proliferation by vascular endothelial growth factor. J Biol Chem 280:33262–33269CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ha CH, Wang W, Jhun BS, Wong C, Hausser A, Pfizenmaier K, McKinsey TA, Olson EN, Jin ZG (2008) Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis. J Biol Chem 283:14590–14599CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Dequiedt F, Van Lint J, Lecomte E, Van Duppen V, Seufferlein T, Vandenheede JR, Wattiez R, Kettmann R (2005) Phosphorylation of histone deacetylase 7 by protein kinase D mediates T cell receptor-induced Nur77 expression and apoptosis. J Exp Med 201:793–804CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bastea LI, Doppler H, Balogun B, Storz P (2012) Protein kinase D1 maintains the epithelial phenotype by inducing a DNA-bound, inactive SNAI1 transcriptional repressor complex. PLoS One 7:e30459CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Zheng H, Shen M, Zha YL, Li W, Wei Y, Blanco MA, Ren G, Zhou T, Storz P, Wang HY, Kang Y (2014) PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. Cancer Cell 26:358–373CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Baron CL, Malhotra V (2002) Role of diacylglycerol in PKD recruitment to the TGN and protein transport to the plasma membrane. Science 295:325–328CrossRefPubMedGoogle Scholar
  19. 19.
    Hausser A, Storz P, Martens S, Link G, Toker A, Pfizenmaier K (2005) Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIβ at the Golgi complex. Nat Cell Biol 7:880–886CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Waldron RT, Rozengurt E (2000) Oxidative stress induces protein kinase D activation in intact cells. Involvement of Src and dependence on protein kinase C. J Biol Chem 275:17114–17121CrossRefPubMedGoogle Scholar
  21. 21.
    Zugaza JL, Sinnett-Smith J, Van Lint J, Rozengurt E (1996) Protein kinase D (PKD) activation in intact cells through a protein kinase C-dependent signal transduction pathway. EMBO J 15:6220–6230PubMedPubMedCentralGoogle Scholar
  22. 22.
    Hao Q, McKenzie R, Gan H, Tang H (2013) Protein kinases D2 and D3 are novel growth regulators in HCC1806 triple-negative breast cancer cells. Anticancer Res 33:393–399PubMedGoogle Scholar
  23. 23.
    Wei N, Chu E, Wipf P, Schmitz JC (2014) Protein kinase d as a potential chemotherapeutic target for colorectal cancer. Mol Cancer Ther 13:1130–1141CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Liou GY, Storz P (2015) Protein kinase D enzymes: novel kinase targets in pancreatic cancer. Expert Rev Gastroenterol Hepatol 9:1143–1146CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Harikumar KB, Kunnumakkara AB, Ochi N, Tong Z, Deorukhkar A, Sung B, Kelland L, Jamieson S, Sutherland R, Raynham T, Charles M, Bagherzadeh A, Foxton C, Boakes A, Farooq M, Maru D, Diagaradjane P, Matsuo Y, Sinnett-Smith J, Gelovani J, Krishnan S, Aggarwal BB, Rozengurt E, Ireson CR, Guha S (2010) A novel small-molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo. Mol Cancer Ther 9:1136–1146CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Durand N, Borges S, Storz P (2016) Protein kinase D enzymes as regulators of EMT and cancer cell invasion. J Clin Med 5:20CrossRefPubMedCentralGoogle Scholar
  27. 27.
    Borges S, Perez EA, Thompson EA, Radisky DC, Geiger XJ, Storz P (2015) Effective targeting of estrogen receptor-negative breast cancers with the protein kinase D inhibitor CRT0066101. Mol Cancer Ther 14:1306–1316CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wei N, Chu E, Wu SY, Wipf P, Schmitz JC (2015) The cytotoxic effects of regorafenib in combination with protein kinase D inhibition in human colorectal cancer cells. Oncotarget 6:4745–4756PubMedGoogle Scholar
  29. 29.
    Verbon EH, Post JA, Boonstra J (2012) The influence of reactive oxygen species on cell cycle progression in mammalian cells. Gene 511:1–6CrossRefPubMedGoogle Scholar
  30. 30.
    Lu Z, Hunter T (2010) Ubiquitylation and proteasomal degradation of the p21(Cip1), p27(Kip1) and p57(Kip2) CDK inhibitors. Cell Cycle 9:2342–2352CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    McDonald ER 3rd, El-Deiry WS (2000) Cell cycle control as a basis for cancer drug development (review). Int J Oncol 16:871–886PubMedGoogle Scholar
  32. 32.
    Lacy ER, Wang Y, Post J, Nourse A, Webb W, Mapelli M, Musacchio A, Siuzdak G, Kriwacki RW (2005) Molecular basis for the specificity of p27 toward cyclin-dependent kinases that regulate cell division. J Mol Biol 349:764–773CrossRefPubMedGoogle Scholar
  33. 33.
    Hu X, Moscinski LC (2011) Cdc2: a monopotent or pluripotent CDK? Cell Prolif 44:205–211CrossRefPubMedGoogle Scholar
  34. 34.
    O’Connell MJ, Walworth NC, Carr AM (2000) The G2-phase DNA-damage checkpoint. Trends Cell Biol 10:296–303CrossRefPubMedGoogle Scholar
  35. 35.
    Brezak MC, Quaranta M, Mondesert O, Galcera MO, Lavergne O, Alby F, Cazales M, Baldin V, Thurieau C, Harnett J, Lanco C, Kasprzyk PG, Prevost GP, Ducommun B (2004) A novel synthetic inhibitor of CDC25 phosphatases: bN82002. Cancer Res 64:3320–3325CrossRefPubMedGoogle Scholar
  36. 36.
    Damia G, Broggini M (2004) Cell cycle checkpoint proteins and cellular response to treatment by anticancer agents. Cell Cycle 3:46–50CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang Y, Hunter T (2014) Roles of Chk1 in cell biology and cancer therapy. Int J Cancer 134:1013–1023CrossRefPubMedGoogle Scholar
  38. 38.
    Perdiguero E, Nebreda AR (2004) Regulation of Cdc25C activity during the meiotic G2/M transition. Cell Cycle 3:733–737CrossRefPubMedGoogle Scholar
  39. 39.
    Mueller PR, Coleman TR, Kumagai A, Dunphy WG (1995) Myt1: a membrane-associated inhibitory kinase that phosphorylates Cdc2 on both threonine-14 and tyrosine-15. Science 270:86–90CrossRefPubMedGoogle Scholar
  40. 40.
    Ruiz EJ, Vilar M, Nebreda AR (2010) A two-step inactivation mechanism of Myt1 ensures CDK1/cyclin B activation and meiosis I entry. Curr Biol 20:717–723CrossRefPubMedGoogle Scholar
  41. 41.
    Den Haese GJ, Walworth N, Carr AM, Gould KL (1995) The Wee1 protein kinase regulates T14 phosphorylation of fission yeast Cdc2. Mol Biol Cell 6:371–385CrossRefGoogle Scholar
  42. 42.
    Watanabe N, Broome M, Hunter T (1995) Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J 14:1878–1891PubMedPubMedCentralGoogle Scholar
  43. 43.
    Parker LL, Sylvestre PJ, Byrnes MJ 3rd, Liu F, Piwnica-Worms H (1995) Identification of a 95-kDa WEE1-like tyrosine kinase in HeLa cells. Proc Natl Acad Sci USA 92:9638–9642CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kawabe T (2004) G2 checkpoint abrogators as anticancer drugs. Mol Cancer Ther 3:513–519PubMedGoogle Scholar
  45. 45.
    Heller JD, Kuo J, Wu TC, Kast WM, Huang RC (2001) Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo. Cancer Res 61:5499–5504PubMedGoogle Scholar
  46. 46.
    Li QQ, Wang G, Liang H, Li JM, Huang F, Agarwal PK, Zhong Y, Reed E (2013) β-Elemene promotes cisplatin-induced cell death in human bladder cancer and other carcinomas. Anticancer Res 33:1421–1428PubMedGoogle Scholar
  47. 47.
    Rotem A, Janzer A, Izar B, Ji Z, Doench JG, Garraway LA, Struhl K (2015) Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation. Proc Natl Acad Sci USA 112:5708–5713CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Cancer Genome Atlas Research N (2014) Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315–322CrossRefGoogle Scholar
  49. 49.
    Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dyrskjot L, Kruhoffer M, Thykjaer T, Marcussen N, Jensen JL, Moller K, Orntoft TF (2004) Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res 64:4040–4048CrossRefPubMedGoogle Scholar
  51. 51.
    Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C (2006) Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 24:778–789CrossRefPubMedGoogle Scholar
  52. 52.
    Blaveri E, Simko JP, Korkola JE, Brewer JL, Baehner F, Mehta K, Devries S, Koppie T, Pejavar S, Carroll P, Waldman FM (2005) Bladder cancer outcome and subtype classification by gene expression. Clin Cancer Res 11:4044–4055CrossRefPubMedGoogle Scholar
  53. 53.
    Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, Hollander MC, O’Connor PM, Fornace AJ Jr, Harris CC (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96:3706–3711CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y (2003) Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345. J Biol Chem 278:25207–25217CrossRefPubMedGoogle Scholar
  55. 55.
    Wang Y, Jacobs C, Hook KE, Duan H, Booher RN, Sun Y (2000) Binding of 14-3-3β to the carboxyl terminus of Wee1 increases Wee1 stability, kinase activity, and G2-M cell population. Cell Growth Differ 11:211–219PubMedGoogle Scholar
  56. 56.
    Rothblum-Oviatt CJ, Ryan CE, Piwnica-Worms H (2001) 14-3-3 Binding regulates catalytic activity of human Wee1 kinase. Cell Growth Differ 12:581–589PubMedGoogle Scholar
  57. 57.
    Eastman A (2004) Cell cycle checkpoints and their impact on anticancer therapeutic strategies. J Cell Biochem 91:223–231CrossRefPubMedGoogle Scholar
  58. 58.
    Sherr CJ (1996) Cancer cell cycles. Science 274:1672–1677CrossRefPubMedGoogle Scholar
  59. 59.
    Dynlacht BD (1997) Regulation of transcription by proteins that control the cell cycle. Nature 389:149–152CrossRefPubMedGoogle Scholar
  60. 60.
    Choi YH, Lee WH, Park KY, Zhang L (2000) p53-independent induction of p21 (WAF1/CIP1), reduction of cyclin B1 and G2/M arrest by the isoflavone genistein in human prostate carcinoma cells. Jpn J Cancer Res 91:164–173CrossRefPubMedGoogle Scholar
  61. 61.
    Lopez-Girona A, Furnari B, Mondesert O, Russell P (1999) Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein. Nature 397:172–175CrossRefPubMedGoogle Scholar
  62. 62.
    Furnari B, Rhind N, Russell P (1997) Cdc25 mitotic inducer targeted by chk1 DNA damage checkpoint kinase. Science 277:1495–1497CrossRefPubMedGoogle Scholar
  63. 63.
    Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277:1497–1501CrossRefPubMedGoogle Scholar
  64. 64.
    Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ Jr (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18:2892–2900CrossRefPubMedGoogle Scholar
  65. 65.
    Vairapandi M, Balliet AG, Hoffman B, Liebermann DA (2002) GADD45b and GADD45g are cdc2/cyclin B1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J Cell Physiol 192:327–338CrossRefPubMedGoogle Scholar
  66. 66.
    Lee J, Kumagai A, Dunphy WG (2001) Positive regulation of Wee1 by Chk1 and 14-3-3 proteins. Mol Biol Cell 12:551–563CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Moore JD, Yang J, Truant R, Kornbluth S (1999) Nuclear import of Cdk/cyclin complexes: identification of distinct mechanisms for import of Cdk2/cyclin E and Cdc2/cyclin B1. J Cell Biol 144:213–224CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Takizawa CG, Weis K, Morgan DO (1999) Ran-independent nuclear import of cyclin B1-Cdc2 by importin β. Proc Natl Acad Sci USA 96:7938–7943CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Hermeking H, Lengauer C, Polyak K, He TC, Zhang L, Thiagalingam S, Kinzler KW, Vogelstein B (1997) 14-3-3σ is a p53-regulated inhibitor of G2/M progression. Mol Cell 1:3–11CrossRefPubMedGoogle Scholar
  70. 70.
    Guweidhi A, Kleeff J, Giese N, El Fitori J, Ketterer K, Giese T, Buchler MW, Korc M, Friess H (2004) Enhanced expression of 14-3-3σ in pancreatic cancer and its role in cell cycle regulation and apoptosis. Carcinogenesis 25:1575–1585CrossRefPubMedGoogle Scholar
  71. 71.
    Courtois S, Caron de Fromentel C, Hainaut P (2004) p53 protein variants: structural and functional similarities with p63 and p73 isoforms. Oncogene 23:631–638CrossRefPubMedGoogle Scholar
  72. 72.
    Draetta G, Eckstein J (1997) Cdc25 protein phosphatases in cell proliferation. Biochim Biophys Acta 1332:M53–M63PubMedGoogle Scholar
  73. 73.
    Izumi T, Maller JL (1993) Elimination of cdc2 phosphorylation sites in the cdc25 phosphatase blocks initiation of M-phase. Mol Biol Cell 4:1337–1350CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Bernhart E, Damm S, Wintersperger A, DeVaney T, Zimmer A, Raynham T, Ireson C, Sattler W (2013) Protein kinase D2 regulates migration and invasion of U87MG glioblastoma cells in vitro. Exp Cell Res 319:2037–2048CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Zou Z, Zeng F, Xu W, Wang C, Ke Z, Wang QJ, Deng F (2012) PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-κB- and HDAC1-mediated expression and activation of uPA. J Cell Sci 125:4800–4811CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Visconti R, Della Monica R, Grieco D (2016) Cell cycle checkpoint in cancer: a therapeutically targetable double-edged sword. J Exp Clin Cancer Res 35:153CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Li QQ, Hao JJ, Zhang Z, Hsu I, Liu Y, Tao Z, Lewi K, Metwalli AR, Agarwal PK (2016) Histone deacetylase inhibitor-induced cell death in bladder cancer is associated with chromatin modification and modifying protein expression: a proteomic approach. Int J Oncol 48:2591–2607CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Li QQ, Hao JJ, Zhang Z, Krane LS, Hammerich KH, Sanford T, Trepel JB, Neckers L, Agarwal PK (2017) Proteomic analysis of proteome and histone post-translational modifications in heat shock protein 90 inhibition-mediated bladder cancer therapeutics. Sci Rep 7:201CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© US Government (outside the USA) 2017

Authors and Affiliations

  • Qingdi Quentin Li
    • 1
  • Iawen Hsu
    • 1
  • Thomas Sanford
    • 1
  • Reema Railkar
    • 1
  • Navin Balaji
    • 1
  • Carole Sourbier
    • 1
  • Cathy Vocke
    • 1
  • K. C. Balaji
    • 2
  • Piyush K. Agarwal
    • 1
  1. 1.Urologic Oncology Branch, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Wake Forest University School of MedicineWinston SalemUSA

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