NES1/KLK10 and hNIS gene therapy enhanced iodine-131 internal radiation in PC3 proliferation inhibition

  • Jiajia Hu
  • Wenbin Shen
  • Qian Qu
  • Xiaochun Fei
  • Ying Miao
  • Xinyun Huang
  • Jiajun Liu
  • Yingli WuEmail author
  • Biao LiEmail author
Research Article


NES1 gene is thought to be a tumor-suppressor gene. Our previous study found that overexpression of NES1 gene in PC3 cell line could slow down the tumor proliferation rate, associated with a mild decrease in BCL-2 expression. The BCL-2 decrease could increase the sensitivity of radiotherapy to tumors. Thus, we supposed to have an “enhanced firepower” effect by combining overexpressed NES1 gene therapy and 131I radiation therapy uptake by overexpressed hNIS protein. We found a weak endogenous expression of hNIS protein in PC3 cells and demonstrated that the low expression of hNIS protein in PC3 cells might be the reason for the low iodine uptake. By overexpressing hNIS in PC3, the radioactive iodine uptake ability was significantly increased. Results of in vitro and in vivo tumor proliferation experiments and 18F-fluorothymidine (18F-FLT) micro-positron emission tomography/computed tomography (micro-PET/CT) imaging showed that the combined NES1 gene therapy and 131I radiation therapy mediated by overexpressed hNIS protein had the best tumor proliferative inhibition effect. Immunohistochemistry showed an obvious decrease of Ki-67 expression and the lowest BCL-2 expression. These data suggest that via inhibition of BCL-2 expression, overexpressed NES1 might enhance the effect of radiation therapy of 131I uptake in hNIS overexpressed PC3 cells.


androgen-independent prostate cancer normal epithelial cell-specific 1/kallikrein 10 sodium/iodide symporter radiation therapy proliferation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This study was financially supported by the foundation from the National Natural Science Foundation of China (Nos. 81501502 and 81570118), Scientific Research Project of Shanghai Municipal Commission of Health and Family Planning (No. 201740154), Multidisciplinary Cross-Project (Medical) of Shanghai Jiao Tong University (No. YG2017MS65), and the foundation of talent plan A for Guangci Excellent Youth of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (No. GCQN-2017-A12), and the National Key R&D Program of China (No. 2017YFA 0505200).


  1. 1.
    Siegel RLMK, Jemal A. Cancer Statistics, 2017. CA Cancer DJ Clin 2017; 67: 23Google Scholar
  2. 2.
    Chen R, Sjoberg DD, Huang Y, Xie L, Zhou L, He D, Vickers AJ, Sun Y; Chinese Prostate Cancer Consortium; Prostate Biopsy Collaborative Group. Prostate specific antigen and prostate cancer in Chinese men undergoing initial prostate biopsies compared with western cohorts. J Urol 2017; 197(1): 90–96CrossRefGoogle Scholar
  3. 3.
    Mohler JL, Kantoff PW, Armstrong AJ, Bahnson RR, Cohen M, D’Amico AV, Eastham JA, Enke CA, Farrington TA, Higano CS, Horwitz EM, Kane CJ, Kawachi MH, Kuettel M, Kuzel TM, Lee RJ, Malcolm AW, Miller D, Plimack ER, Pow-Sang JM, Raben D, Richey S, Roach M 3rd, Rohren E, Rosenfeld S, Schaeffer E, Small EJ, Sonpavde G, Srinivas S, Stein C, Strope SA, Tward J, Shead DA, Ho M; National Comprehensive Cancer Network. Prostate cancer, version 2.2014. J Natl Compr Canc Netw 2014; 12(5): 686–718CrossRefGoogle Scholar
  4. 4.
    Heidenreich A, Aus G, Bolla M, Joniau S, Matveev VB, Schmid HP, Zattoni F; European Association of Urology. EAU guidelines on prostate cancer. Eur Urol 2008; 53(1): 68–80CrossRefGoogle Scholar
  5. 5.
    Williams SB, Huo J, Chamie K, Smaldone MC, Kosarek CD, Fang JE, Ynalvez LA, Kim SP, Hoffman KE, Giordano SH, Chapin BF. Discerning the survival advantage among patients with prostate cancer who undergo radical prostatectomy or radiotherapy: the limitations of cancer registry data. Cancer 2017; 123(9): 1617–1624CrossRefGoogle Scholar
  6. 6.
    Pagliarulo V, Bracarda S, Eisenberger MA, Mottet N, Schröder FH, Sternberg CN, Studer UE. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol 2012; 61(1): 11–25CrossRefGoogle Scholar
  7. 7.
    Bolla M, de Reijke TM, Van Tienhoven G, Van den Bergh AC, Oddens J, Poortmans PM, Gez E, Kil P, Akdas A, Soete G, Kariakine O, van der Steen-Banasik EM, Musat E, Piérart M, Mauer ME, Collette L; EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009; 360(24): 2516–2527CrossRefGoogle Scholar
  8. 8.
    Amaral TM, Macedo D, Fernandes I, Costa L. Castration-resistant prostate cancer: mechanisms, targets, and treatment. Prostate Cancer 2012; 2012: 327253CrossRefGoogle Scholar
  9. 9.
    Basch E, Loblaw DA, Oliver TK, Carducci M, Chen RC, Frame JN, Garrels K, Hotte S, Kattan MW, Raghavan D, Saad F, Taplin ME, Walker-Dilks C, Williams J, Winquist E, Bennett CL, Wootton T, Rumble RB, Dusetzina SB, Virgo KS. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol 2014; 32(30): 3436–3448CrossRefGoogle Scholar
  10. 10.
    Zhang T, Zhu J, George DJ, Armstrong AJ. Enzalutamide versus abiraterone acetate for the treatment of men with metastatic castration-resistant prostate cancer. Expert Opin Pharmacother 2015; 16(4): 473–485CrossRefGoogle Scholar
  11. 11.
    Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161(5): 1215–1228CrossRefGoogle Scholar
  12. 12.
    Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 2015; 163: 1011–1025CrossRefGoogle Scholar
  13. 13.
    Liu XL, Wazer DE, Watanabe K, Band V. Identification of a novel serine protease-like gene, the expression of which is down-regulated during breast cancer progression. Cancer Res 1996; 56(14): 3371–3379Google Scholar
  14. 14.
    Hu J, Lei H, Fei X, Liang S, Xu H, Qin D, Wang Y, Wu Y, Li B. NES1/KLK10 gene represses proliferation, enhances apoptosis and down-regulates glucose metabolism of PC3 prostate cancer cells. Sci Rep 2015; 5(1): 17426CrossRefGoogle Scholar
  15. 15.
    Czabotar PE, Lessene G, Strasser A, Adams JM. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15(1): 49–63CrossRefGoogle Scholar
  16. 16.
    Zhang D, Cui Y, Niu L, Xu X, Tian K, Young CY, Lou H, Yuan H. Regulation of SOD2 and β-arrestin1 by interleukin-6 contributes to the increase of IGF-1R expression in docetaxel resistant prostate cancer cells. Eur J Cell Biol 2014; 93(7): 289–298CrossRefGoogle Scholar
  17. 17.
    Rajecki M, Sarparanta M, Hakkarainen T, Tenhunen M, Diaconu I, Kuhmonen V, Kairemo K, Kanerva A, Airaksinen AJ, Hemminki A. SPECT/CT imaging of hNIS-expression after intravenous delivery of an oncolytic adenovirus and 131I. PLoS One 2012; 7(3): e32871CrossRefGoogle Scholar
  18. 18.
    Barton KN, Stricker H, Elshaikh MA, Pegg J, Cheng J, Zhang Y, Karvelis KC, Lu M, Movsas B, Freytag SO. Feasibility of adenovirus-mediated hNIS gene transfer and 131I radioiodine therapy as a definitive treatment for localized prostate cancer. Mol Ther 2011; 19(7): 1353–1359CrossRefGoogle Scholar
  19. 19.
    Chen X, Wong JY, Wong P, Radany EH. Low-dose valproic acid enhances radiosensitivity of prostate cancer through acetylated p53-dependent modulation of mitochondrial membrane potential and apoptosis. Mol Cancer Res 2011; 9(4): 448–461CrossRefGoogle Scholar
  20. 20.
    Ezekwudo D, Shashidharamurthy R, Devineni D, Bozeman E, Palaniappan R, Selvaraj P. Inhibition of expression of anti-apoptotic protein Bcl-2 and induction of cell death in radioresistant human prostate adenocarcinoma cell line (PC-3) by methyl jasmonate. Cancer Lett 2008; 270(2): 277–285CrossRefGoogle Scholar
  21. 21.
    Goyal J, Smith KM, Cowan JM, Wazer DE, Lee SW, Band V. The role for NES1 serine protease as a novel tumor suppressor. Cancer Res 1998; 58(21): 4782–4786Google Scholar
  22. 22.
    Li B, Goyal J, Dhar S, Dimri G, Evron E, Sukumar S, Wazer DE, Band V. CpG methylation as a basis for breast tumor-specific loss of NES1/kallikrein 10 expression. Cancer Res 2001; 61(21): 8014–8021Google Scholar
  23. 23.
    Ahmed KA, Davis BJ, Wilson TM, Wiseman GA, Federspiel MJ, Morris JC. Progress in gene therapy for prostate cancer. Front Oncol 2012; 2: 172CrossRefGoogle Scholar
  24. 24.
    Spitzweg C, Dietz AB, O’Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC. In vivo sodium iodide symporter gene therapy of prostate cancer. Gene Ther 2001; 8(20): 1524–1531CrossRefGoogle Scholar
  25. 25.
    Trujillo MA, Oneal MJ, McDonough S, Qin R, Morris JC. A steep radioiodine dose response scalable to humans in sodium-iodide symporter (NIS)-mediated radiovirotherapy for prostate cancer. Cancer Gene Ther 2012; 19(12): 839–844CrossRefGoogle Scholar
  26. 26.
    Zhao LM, Pang AX. Iodine-131 treatment of thyroid cancer cells leads to suppression of cell proliferation followed by induction of cell apoptosis and cell cycle arrest by regulation of B-cell translocation gene 2-mediated JNK/NF-κB pathways. Braz J Med Biol Res 2017; 50(1): e5933CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jiajia Hu
    • 1
  • Wenbin Shen
    • 1
  • Qian Qu
    • 1
  • Xiaochun Fei
    • 2
  • Ying Miao
    • 1
  • Xinyun Huang
    • 1
  • Jiajun Liu
    • 1
  • Yingli Wu
    • 3
    Email author
  • Biao Li
    • 1
    Email author
  1. 1.Department of Nuclear MedicineRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
  2. 2.Department of PathologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina
  3. 3.Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghaiChina

Personalised recommendations