Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Statins reduce castration-induced bone marrow adiposity and prostate cancer progression in bone

Oncogene volume 40, pages 4592–4603 (2021)Cite this article

Subjects

Abstract

A fraction of patients undergoing androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) will develop recurrent castrate-resistant PCa (CRPC) in bone. Strategies to prevent CRPC relapse in bone are lacking. Here we show that the cholesterol-lowering drugs statins decrease castration-induced bone marrow adiposity in the tumor microenvironment and reduce PCa progression in bone. Using primary bone marrow stromal cells (BMSC) and M2-10B4 cells, we showed that ADT increases bone marrow adiposity by enhancing BMSC-to-adipocyte transition in vitro. Knockdown of androgen receptor abrogated BMSC-to-adipocyte transition, suggesting an androgen receptor-dependent event. RNAseq analysis showed that androgens reduce the secretion of adipocyte hormones/cytokines including leptin during BMSC-to-adipocyte transition. Treatment of PCa C4-2b, C4-2B4, and PC3 cells with leptin led to an increase in cell cycle progression and nuclear Stat3. RNAseq analysis also showed that androgens inhibit cholesterol biosynthesis pathway, raising the possibility that inhibiting cholesterol biosynthesis may decrease BMSC-to-adipocyte transition. Indeed, statins decreased BMSC-to-adipocyte transition in vitro and castration-induced bone marrow adiposity in vivo. Statin pre-treatment reduced 22RV1 PCa progression in bone after ADT. Our findings with statin may provide one of the mechanisms to the clinical correlations that statin use in patients undergoing ADT seems to delay progression to “lethal” PCa.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Castration enhances while androgens suppress BMSC-to-adipocyte transition.
Fig. 2: Androgen receptor mediates suppression of BMSC-to-adipocyte transition by DHT.
Fig. 3: RNAseq analysis of changes in gene expression during BMSC-to-adipocyte transition with or without DHT treatment.
Fig. 4: Adipocyte-conditioned medium and leptin stimulate prostate cancer cell cycle progression and cell proliferation.
Fig. 5: Statins inhibit BMSC-to-adipocyte transition in vitro.
Fig. 6: Statins suppress BMSC-to-adipocyte transition and reduce prostate cancer progression in bone in vivo.

Similar content being viewed by others

Data availability

The RNAseq data have been deposited. The GEO accession number is “GSE174516”.

References

  1. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655–64.

    Article  CAS  PubMed  Google Scholar 

  3. Logothetis CJ, Gallick GE, Maity SN, Kim J, Aparicio A, Efstathiou E, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discov. 2013;3:849–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Platz EA, Leitzmann MF, Visvanathan K, Rimm EB, Stampfer MJ, Willett WC, et al. Statin drugs and risk of advanced prostate cancer. J Natl Cancer Inst. 2006;98:1819–25.

    Article  CAS  PubMed  Google Scholar 

  5. Gordon JA, Buonerba C, Pond G, Crona D, Gillessen S, Lucarelli G, et al. Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study. Oncotarget. 2018;9:19861–73.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Harshman LC, Wang X, Nakabayashi M, Xie W, Valenca L, Werner L, et al. Statin use at the time of initiation of androgen deprivation therapy and time to progression in patients with hormone-sensitive prostate cancer. JAMA Oncol. 2015;1:495–504.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol. 2017;14:107–19.

    Article  CAS  PubMed  Google Scholar 

  8. Lee YC, Lin SC, Yu G, Cheng CJ, Liu B, Liu HC, et al. Identification of bone-derived factors conferring de novo therapeutic resistance in metastatic prostate cancer. Cancer Res. 2015;75:4949–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Logothetis C, Lin S-H. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005;5:21–8.

    Article  CAS  PubMed  Google Scholar 

  10. Calvi LM, Link DC. The hematopoietic stem cell niche in homeostasis and disease. Blood. 2015;126:2443–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Diedrich J, Gusky HC, Podgorski I. Adipose tissue dysfunction and its effects on tumor metabolism. Horm Mol Biol Clin Investig. 2015;21:17–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Herroon MK, Rajagurubandara E, Hardaway AL, Powell K, Turchick A, Feldmann D, et al. Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. Oncotarget. 2013;4:2108–23.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sharifi N, Gulley JL, Dahut WL. An update on androgen deprivation therapy for prostate cancer. Endocr Relat Cancer. 2010;17:R305–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gimble JM, Robinson CE, Wu X, Kelly KA. The function of adipocytes in the bone marrow stroma: an update. Bone. 1996;19:421–8.

    Article  CAS  PubMed  Google Scholar 

  15. Tencerova M, Kassem M. The bone marrow-derived stromal cells: commitment and regulation of adipogenesis. Front Endocrinol (Lausanne). 2016;7:127.

    Article  Google Scholar 

  16. Sutherland HJ, Eaves CJ, Lansdorp PM, Thacker JD, Hogge DE. Differential regulation of primitive human hematopoietic cells in long-term cultures maintained on genetically engineered murine stromal cells. Blood. 1991;78:666–72.

    Article  CAS  PubMed  Google Scholar 

  17. Lucas-Herald AK, Alves-Lopes R, Montezano AC, Ahmed SF, Touyz RM. Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications. Clin Sci (Lond). 2017;131:1405–18.

    Article  CAS  Google Scholar 

  18. Lin D, Alberton P, Caceres MD, Volkmer E, Schieker M, Docheva D. Tenomodulin is essential for prevention of adipocyte accumulation and fibrovascular scar formation during early tendon healing. Cell Death Dis. 2017;8:e3116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sato K, Emi M, Ezura Y, Fujita Y, Takada D, Ishigami T, et al. Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. J Hum Genet. 2004;49:29–34.

    Article  CAS  PubMed  Google Scholar 

  20. Sakaue-Sawano A, Kurokawa H, Morimura T, Hanyu A, Hama H, Osawa H, et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell. 2008;132:487–98.

    Article  CAS  PubMed  Google Scholar 

  21. Saxena NK, Vertino PM, Anania FA, Sharma D. leptin-induced growth stimulation of breast cancer cells involves recruitment of histone acetyltransferases and mediator complex to CYCLIN D1 promoter via activation of Stat3. J Biol Chem. 2007;282:13316–25.

    Article  CAS  PubMed  Google Scholar 

  22. Azemawah V, Movahed MR, Centuori P, Penaflor R, Riel PL, Situ S, et al. State of the art comprehensive review of individual statins, their differences, pharmacology, and clinical implications. Cardiovasc Drugs Ther. 2019;33:625–39.

    Article  CAS  PubMed  Google Scholar 

  23. Goto T, Nagai H, Egawa K, Kim YI, Kato S, Taimatsu A, et al. Farnesyl pyrophosphate regulates adipocyte functions as an endogenous PPARgamma agonist. Biochem J. 2011;438:111–9.

    Article  CAS  PubMed  Google Scholar 

  24. Xu L, Shen M, Chen X, Zhu R, Yang DR, Tsai Y, et al. Adipocytes affect castration-resistant prostate cancer cells to develop the resistance to cytotoxic action of NK cells with alterations of PD-L1/NKG2D ligand levels in tumor cells. Prostate. 2018;78:353–64.

    Article  CAS  PubMed  Google Scholar 

  25. Laurent V, Guerard A, Mazerolles C, Le Gonidec S, Toulet A, Nieto L, et al. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nat Commun. 2016;7:10230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Laurent V, Toulet A, Attane C, Milhas D, Dauvillier S, Zaidi F, et al. Periprostatic adipose tissue favors prostate cancer cell invasion in an obesity-dependent manner: role of oxidative stress. Mol Cancer Res. 2019;17:821–35.

    Article  CAS  PubMed  Google Scholar 

  27. Tang KD, Liu J, Jovanovic L, An J, Hill MM, Vela I, et al. Adipocytes promote prostate cancer stem cell self-renewal through amplification of the cholecystokinin autocrine loop. Oncotarget. 2016;7:4939–48.

    Article  PubMed  Google Scholar 

  28. Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Huttemann M, Podgorski I. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation. Oncotarget. 2016;7:64854–77.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tavassoli M. Marrow adipose cells. Ultrastructural and histochemical characterization. Arch Pathol. 1974;98:189–92.

    CAS  PubMed  Google Scholar 

  30. Tavassoli M. Ultrastructural development of bone marrow adipose cell. Acta Anat (Basel). 1976;94:65–77.

    Article  CAS  Google Scholar 

  31. Caers J, Deleu S, Belaid Z, De Raeve H, Van Valckenborgh E, De Bruyne E, et al. Neighboring adipocytes participate in the bone marrow microenvironment of multiple myeloma cells. Leukemia. 2007;21:1580–4.

    Article  CAS  PubMed  Google Scholar 

  32. Liu Z, Xu J, He J, Liu H, Lin P, Wan X, et al. Mature adipocytes in bone marrow protect myeloma cells against chemotherapy through autophagy activation. Oncotarget. 2015;6:34329–41.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev. 2014;33:527–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Morris EV, Edwards CM. Adipokines, adiposity, and bone marrow adipocytes: dangerous accomplices in multiple myeloma. J Cell Physiol. 2018;233:9159–66.

    Article  CAS  PubMed  Google Scholar 

  35. Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis. 2015;32:353–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Abu EO, Horner A, Kusec V, Triffitt JT, Compston JE. The localization of androgen receptors in human bone. J Clin Endocrinol Metab. 1997;82:3493–7.

    Article  CAS  PubMed  Google Scholar 

  37. Mantalaris A, Panoskaltsis N, Sakai Y, Bourne P, Chang C, Messing EM, et al. Localization of androgen receptor expression in human bone marrow. J Pathol. 2001;193:361–6.

    Article  CAS  PubMed  Google Scholar 

  38. Crnalic S, Hornberg E, Wikstrom P, Lerner UH, Tieva A, Svensson O, et al. Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients. Endocr Relat Cancer. 2010;17:885–95.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang Y, Dallner OS, Nakadai T, Fayzikhodjaeva G, Lu YH, Lazar MA, et al. A noncanonical PPARgamma/RXRalpha-binding sequence regulates leptin expression in response to changes in adipose tissue mass. Proc Natl Acad Sci USA. 2018;115:E6039–E6047.

    PubMed  PubMed Central  Google Scholar 

  40. Ottewell PD, Wang N, Meek J, Fowles CA, Croucher PI, Eaton CL, et al. Castration-induced bone loss triggers growth of disseminated prostate cancer cells in bone. Endocr Relat Cancer. 2014;21:769–81.

    Article  CAS  PubMed  Google Scholar 

  41. Sato S, Futakuchi M, Ogawa K, Asamoto M, Nakao K, Asai K, et al. Transforming growth factor beta derived from bone matrix promotes cell proliferation of prostate cancer and osteoclast activation-associated osteolysis in the bone microenvironment. Cancer Sci. 2008;99:316–23.

    Article  CAS  PubMed  Google Scholar 

  42. Jiao S, Subudhi SK, Aparicio A, Ge Z, Guan B, Miura Y, et al. Differences in tumor microenvironment dictate T helper lineage polarization and response to immune checkpoint therapy. Cell. 2019;179:1177–90.e13.

    Article  CAS  PubMed  Google Scholar 

  43. Wu TT, Sikes RA, Cui Q, Thalmann GN, Kao C, Murphy CF, et al. Establishing human prostate cancer cell xenografts in bone: induction of osteoblastic reaction by prostate-specific antigen-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int J Cancer. 1998;77:887–94.

    Article  CAS  PubMed  Google Scholar 

  44. Thalmann GN, Sikes RA, Wu TT, Degeorges A, Chang SM, Ozen M, et al. LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate. 2000;44:91–103.

    Article  CAS  PubMed  Google Scholar 

  45. Thalmann GN, Anezinis PE, Chang S, Zhau HE, Kim E, Hopwood VL, et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 1994;54:2577–81.

    CAS  PubMed  Google Scholar 

  46. Wainstein MA, He F, Robinson D, Kung HJ, Schwartz S, Giaconia JM, et al. CWR22: androgen-dependent xenograft model derived from a primary human prostatic carcinoma. Cancer Res. 1994;54:6049–52.

    CAS  PubMed  Google Scholar 

  47. Sramkoski RM, Pretlow TG 2nd, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, et al. A new human prostate carcinoma cell line, 22Rv1. In Vitro Cell Dev Biol Anim. 1999;35:403–9.

    Article  CAS  PubMed  Google Scholar 

  48. Yu-Lee LY, Yu G, Lee YC, Lin SC, Pan J, Pan T, et al. Osteoblast-secreted factors mediate dormancy of metastatic prostate cancer in the bone via activation of the TGFbetaRIII-p38MAPK-pS249/T252RB pathway. Cancer Res. 2018;78:2911–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lee YC, Jin JK, Cheng CJ, Huang CF, Song JH, Huang M, et al. Targeting constitutively activated beta1 integrins inhibits prostate cancer metastasis. Mol Cancer Res. 2013;11:405–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the NIH (CA174798, P50 CA140388, P30 CA016672), Cancer Prevention and Research Institute of Texas (CPRIT RP150179, RP190252), the Prostate Cancer Foundation, and funds from The University of Texas MD Anderson Moonshot Program.

Author information

Author notes

  1. These authors contributed equally: Tianhong Pan, Song-Chang Lin, Yu-Chen Lee.

Authors and Affiliations

  1. Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Tianhong Pan & Robert L. Satcher

  2. Department of Translational Molecular Pathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Song-Chang Lin, Yu-Chen Lee, Guoyu Yu, Jing Pan & Sue-Hwa Lin

  3. Department of Genitourinary Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Jian H. Song, Mark Titus, Theocharis Panaretakis, Christopher Logothetis & Sue-Hwa Lin

  4. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Li-Yuan Yu-Lee

Authors
  1. Tianhong Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Song-Chang Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Chen Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guoyu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian H. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jing Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark Titus
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert L. Satcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Theocharis Panaretakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher Logothetis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Li-Yuan Yu-Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Sue-Hwa Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sue-Hwa Lin.

Ethics declarations

Competing interests

C.L. reports receiving commercial research grants from Bayer, Sanofi, Janssen, Astellas Pharma, Pfizer; and honoraria from Bayer, Janssen, Sanofi, Astellas Pharma. The other authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pan, T., Lin, SC., Lee, YC. et al. Statins reduce castration-induced bone marrow adiposity and prostate cancer progression in bone. Oncogene 40, 4592–4603 (2021). https://doi.org/10.1038/s41388-021-01874-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-01874-7

This article is cited by

Search

Advanced search

Quick links