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Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model

Oncogene volume 38, pages 6338–6353 (2019)Cite this article

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Abstract

High circulating insulin-like growth factor-1 (IGF-1) levels increase the risk of prostate cancer. However, whether circulating IGF-1 levels directly aggravate prostate cancer remains elusive. In this study, we crossed a transgenic prostate adenocarcinoma mouse model, Hi-Myc mice, with a liver-specific IGF-1 transgenic mouse model (HIT) to increase their circulating IGF-1 levels to investigate the impact of the elevated circulating IGF-1 on prostate cancer development in vivo. The Hi-Myc/HIT mice had increased incidence and invasiveness of prostate cancer. IGF-1 elevation led to the accumulation of FOXO3A in the cytosol of prostate tumor cells and downregulation of its target gene Bim, which resulted in the apoptosis inhibition and prostate cancer overgrowth. The differential expressions of IGF-1R, FOXO3A, and BIM in the benign versus malignant prostate tissues supported a negative association between the FOXO3A/BIM axis and IGF-1R expression in human prostate adenocarcinoma. Our findings suggest that targeting the IGF-1/FOXO3A/BIM signaling axis could be an attractive strategy for prostate cancer prevention or treatment.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.

    Article  Google Scholar 

  2. Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature. 2009;461:495–500.

    Article  CAS  Google Scholar 

  3. Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl J Med. 2003;349:366–81.

    Article  CAS  Google Scholar 

  4. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28:20–47.

    Article  CAS  Google Scholar 

  5. Bonilla C, Lewis SJ, Rowlands MA, Gaunt TR, Davey Smith G, Gunnell D, et al. Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels. Int J Cancer. 2016;139:1520–33.

    Article  CAS  Google Scholar 

  6. Le Roith D. The insulin-like growth factor system. Exp Diabesity Res. 2003;4:205–12.

    Article  Google Scholar 

  7. Macaulay VM. Insulin-like growth factors and cancer. Br J Cancer. 1992;65:311–20.

    Article  CAS  Google Scholar 

  8. DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice. Proc Natl Acad Sci USA. 2000;97:3455–60.

    Article  CAS  Google Scholar 

  9. Cao Y, Nimptsch K, Shui IM, Platz EA, Wu K, Pollak MN, et al. Prediagnostic plasma IGFBP-1, IGF-1 and risk of prostate cancer. Int J Cancer. 2015;136:2418–26.

    Article  CAS  Google Scholar 

  10. Travis RC, Appleby PN, Martin RM, Holly JM, Albanes D, Black A, et al. A meta-analysis of individual participant data reveals an association between circulating levels of IGF-I and prostate cancer risk. Cancer Res. 2016;76:2288–300.

    Article  CAS  Google Scholar 

  11. Shariat SF, Bergamaschi F, Adler HL, Nguyen C, Kattan MW, Wheeler TM, et al. Correlation of preoperative plasma IGF-I levels with pathologic parameters and progression in patients undergoing radical prostatectomy. Urology. 2000;56:423–9.

    Article  CAS  Google Scholar 

  12. Weiss JM, Huang WY, Rinaldi S, Fears TR, Chatterjee N, Chia D, et al. IGF-1 and IGFBP-3: risk of prostate cancer among men in the prostate, lung, colorectal and ovarian cancer screening trial. Int J Cancer. 2007;121:2267–73.

    Article  CAS  Google Scholar 

  13. Dansen TB, Burgering BM. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol. 2008;18:421–9.

    Article  CAS  Google Scholar 

  14. Gross DN, Wan M, Birnbaum MJ. The role of FOXO in the regulation of metabolism. Curr Diab Rep. 2009;9:208–14.

    Article  CAS  Google Scholar 

  15. Lynch RL, Konicek BW, McNulty AM, Hanna KR, Lewis JE, Neubauer BL, et al. The progression of LNCaP human prostate cancer cells to androgen independence involves decreased FOXO3a expression and reduced p27KIP1 promoter transactivation. Mol Cancer Res. 2005;3:163–9.

    Article  CAS  Google Scholar 

  16. Dijkers PF, Medema RH, Lammers JW, Koenderman L, Coffer PJ. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr Biol. 2000;10:1201–4.

    Article  CAS  Google Scholar 

  17. Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res. 2008;68:7661–9.

    Article  CAS  Google Scholar 

  18. Wu Y, Sun H, Yakar S, LeRoith D. Elevated levels of insulin-like growth factor (IGF)-I in serum rescue the severe growth retardation of IGF-I null mice. Endocrinology. 2009;150:4395–403.

    Article  CAS  Google Scholar 

  19. Ellwood-Yen K, Graeber TG, Wongvipat J, Iruela-Arispe ML, Zhang J, Matusik R, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell. 2003;4:223–38.

    Article  CAS  Google Scholar 

  20. Sarwar S, Adil MA, Nyamath P, Ishaq M. Biomarkers of prostatic cancer: an attempt to categorize patients into prostatic carcinoma, benign prostatic hyperplasia, or prostatitis based on serum prostate specific antigen, prostatic acid phosphatase, calcium, and phosphorus. Prostate Cancer. 2017;2017:5687212.

    Article  Google Scholar 

  21. Ali TZ, Epstein JI. False positive labeling of prostate cancer with high molecular weight cytokeratin: p63 a more specific immunomarker for basal cells. Am J Surg Pathol. 2008;32:1890–5.

    Article  Google Scholar 

  22. Powell WC, Cardiff RD, Cohen MB, Miller GJ, Roy-Burman P. Mouse strains for prostate tumorigenesis based on genes altered in human prostate cancer. Curr Drug Targets. 2003;4:263–79.

    Article  CAS  Google Scholar 

  23. Jin R, Yi Y, Yull FE, Blackwell TS, Clark PE, Koyama T, et al. NF-kappaB gene signature predicts prostate cancer progression. Cancer Res. 2014;74:2763–72.

    Article  CAS  Google Scholar 

  24. Shappell SB, Thomas GV, Roberts RL, Herbert R, Ittmann MM, Rubin MA, et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 2004;64:2270–305.

    Article  CAS  Google Scholar 

  25. Das TP, Suman S, Alatassi H, Ankem MK, Damodaran C. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer. Cell Death Dis. 2016;7:e2111.

    Article  CAS  Google Scholar 

  26. Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E, et al. Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells. J Biol Chem. 2005;280:33558–65.

    Article  CAS  Google Scholar 

  27. Rinner O, Mueller LN, Hubalek M, Muller M, Gstaiger M, Aebersold R. An integrated mass spectrometric and computational framework for the analysis of protein interaction networks. Nat Biotechnol. 2007;25:345–52.

    Article  CAS  Google Scholar 

  28. Li PF, Dietz R, von Harsdorf R. p53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO J. 1999;18:6027–36.

    Article  CAS  Google Scholar 

  29. Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309–12.

    Article  CAS  Google Scholar 

  30. Kaplan-Lefko PJ, Sutherland BW, Evangelou AI, Hadsell DL, Barrios RJ, Foster BA, et al. Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. Oncogene. 2008;27:2868–76.

    Article  CAS  Google Scholar 

  31. Sutherland BW, Knoblaugh SE, Kaplan-Lefko PJ, Wang F, Holzenberger M, Greenberg NM. Conditional deletion of insulin-like growth factor-I receptor in prostate epithelium. Cancer Res. 2008;68:3495–504.

    Article  CAS  Google Scholar 

  32. Yakar S, Pennisi P, Zhao H, Zhang Y, LeRoith D. Circulating IGF-1 and its role in cancer: lessons from the IGF-1 gene deletion (LID) mouse. Novartis Found Symp. 2004;262:3–9. discussion 9–18, 265–8

    CAS  PubMed  Google Scholar 

  33. Cannata D, Lann D, Wu Y, Elis S, Sun H, Yakar S, et al. Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology. 2010;151:5751–61.

    Article  CAS  Google Scholar 

  34. Wu Y, Yakar S, Zhao L, Hennighausen L, LeRoith D. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res. 2002;62:1030–5.

    CAS  PubMed  Google Scholar 

  35. Sun J, Lu Z, Deng Y, Wang W, He Q, Yan W, et al. Up-regulation of INSR/IGF1R by C-myc promotes TSCC tumorigenesis and metastasis through the NF-kappaB pathway. Biochim Biophys Acta. 2018;1864:1873–82.

    Article  CAS  Google Scholar 

  36. Butler AA, Blakesley VA, Poulaki V, Tsokos M, Wood TL, LeRoith D. Stimulation of tumor growth by recombinant human insulin-like growth factor-I (IGF-I) is dependent on the dose and the level of IGF-I receptor expression. Cancer Res. 1998;58:3021–7.

    CAS  PubMed  Google Scholar 

  37. Osuka S, Sampetrean O, Shimizu T, Saga I, Onishi N, Sugihara E, et al. IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells. Stem Cells. 2013;31:627–40.

    Article  CAS  Google Scholar 

  38. Imada K, Shiota M, Kuroiwa K, Sugimoto M, Abe T, Kohashi K, et al. FOXO3a expression regulated by ERK signaling is inversely correlated with Y-Box binding protein-1 expression in prostate cancer. Prostate. 2017;77:145–53.

    Article  CAS  Google Scholar 

  39. Dey P, Strom A, Gustafsson JA. Estrogen receptor beta upregulates FOXO3a and causes induction of apoptosis through PUMA in prostate cancer. Oncogene. 2014;33:4213–25.

    Article  CAS  Google Scholar 

  40. Sunters A, Fernandez de Mattos S, Stahl M, Brosens JJ, Zoumpoulidou G, Saunders CA, et al. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem. 2003;278:49795–805.

    Article  CAS  Google Scholar 

  41. Essafi A, Fernandez de Mattos S, Hassen YA, Soeiro I, Mufti GJ, Thomas NS, et al. Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells. Oncogene. 2005;24:2317–29.

    Article  CAS  Google Scholar 

  42. Nandana S, Ellwood-Yen K, Sawyers C, Wills M, Weidow B, Case T, et al. Hepsin cooperates with MYC in the progression of adenocarcinoma in a prostate cancer mouse model. Prostate. 2010;70:591–600.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Grabowska MM, DeGraff DJ, Yu X, Jin RJ, Chen Z, Borowsky AD, et al. Mouse models of prostate cancer: picking the best model for the question. Cancer Metast Rev. 2014;33:377–97.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the Nature Science Foundation of China (NSFC) No. 81471000, No. 31871163, and Ministry of Science and Technology (No. 2014DFA32120) to Yingjie Wu.

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Author notes

  1. These authors contributed equally: Shuang Wang, Ning Wang

Authors and Affiliations

  1. Institute of Genome Engineered Animal Models for Human Diseases, Dalian Medical University, Dalian, Liaoning, 116044, China

    Shuang Wang, Ning Wang, Bin Yu, Mingxing Cao, Li Zeng & Yingjie Wu

  2. National Center of Genetically Engineered Animal Models for International Research, Dalian Medical University, Dalian, Liaoning, 116044, China

    Shuang Wang, Ning Wang, Bin Yu, Mingxing Cao, Li Zeng & Yingjie Wu

  3. College of Integrative Medicine, Dalian Medical University, Dalian, Liaoning, 116044, China

    Shuang Wang, Ning Wang & Yingjie Wu

  4. College of Life Science and Technology, Mudanjiang Normal University, Mudanjiang, Heilongjiang, 157011, China

    Mingxing Cao

  5. Department of Urology Surgery, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, 116033, China

    Yanlong Wang

  6. Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, 10010, USA

    Yuqi Guo, Yanli Zhang, Xin Li & Yingjie Wu

  7. Department of Endocrinology, Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116027, China

    Ping Zhang

  8. Department of Pathology, Dalian Medical University, Dalian, Liaoning, 116044, China

    Xiao Yu

  9. Department of Biochemistry and Molecular Biology, Dalian Medical University, Dalian, Liaoning, 116044, China

    Shujing Wang

  10. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, CAS Center for Excellence in Animal Evolution and Genetics, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China

    Bin Liang

  11. Department of Urology, New York University Langone Medical Center, New York, NY, 10016, USA

    Xin Li

  12. Perlmutter Cancer Institute, New York University Langone Medical Center, New York, NY, 10016, USA

    Xin Li

  13. Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York, NY, 10029, USA

    Yingjie Wu

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  1. Shuang Wang
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Correspondence to Bin Liang, Xin Li or Yingjie Wu.

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Wang, S., Wang, N., Yu, B. et al. Circulating IGF-1 promotes prostate adenocarcinoma via FOXO3A/BIM signaling in a double-transgenic mouse model. Oncogene 38, 6338–6353 (2019). https://doi.org/10.1038/s41388-019-0880-9

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