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.

Melatonin interrupts osteoclast functioning and suppresses tumor-secreted RANKL expression: implications for bone metastases

Abstract

Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Melatonin regulates osteoclast differentiation.
Fig. 2: Melatonin affects the functions of mature osteoclasts.
Fig. 3: Melatonin regulates tumor-associated osteoclastogenesis.
Fig. 4: Melatonin regulates RANKL production in cancer cells.
Fig. 5: Melatonin affects in vivo tumor growth and bone erosion.
Fig. 6: Schema depicting the effects of melatonin in osteolytic bone disease.

References

  1. 1.

    Chin H, Kim J. Bone Metastasis: Concise Overview. Fed Pract: Health Care Prof VA, DoD, PHS. 2015;32:24–30.

    Google Scholar 

  2. 2.

    Singh VA, Haseeb A, Alkubaisi AA. Incidence and outcome of bone metastatic disease at University Malaya Medical Centre. Singap Med J. 2014;55:539–46.

    Google Scholar 

  3. 3.

    Svensson E, Christiansen CF, Ulrichsen SP, Rorth MR, Sorensen HT. Survival after bone metastasis by primary cancer type: a Danish population-based cohort study. BMJ Open. 2017;7:e016022.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone metastases: an overview. Oncol Rev. 2017;11:321.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Schmid-Alliana A, Schmid-Antomarchi H, Al-Sahlanee R, Lagadec P, Scimeca JC, Verron E. Understanding the progression of bone metastases to identify novel therapeutic targets. Int J Mol Sci. 2018;19:148.

    PubMed Central  Google Scholar 

  6. 6.

    Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. Molecular biology of bone metastasis. Mol Cancer Ther. 2007;6:2609–17.

    CAS  PubMed  Google Scholar 

  7. 7.

    Lyu H, Jundi B, Xu C, Tedeschi SK, Yoshida K, Zhao S, et al. Comparison of Denosumab and Bisphosphonates in patients with osteoporosis: a meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2019;104:1753–65.

    PubMed  Google Scholar 

  8. 8.

    Steger GG, Bartsch R. Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion. Ther Adv Med Oncol. 2011;3:233–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Benjamin B, Benjamin MA, Swe M, Sugathan S. Review on the comparison of effectiveness between denosumab and bisphosphonates in post-menopausal osteoporosis. Osteoporos Sarcopenia. 2016;2:77–81.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Wutzl A, Eisenmenger G, Hoffmann M, Czerny C, Moser D, Pietschmann P, et al. Osteonecrosis of the jaws and bisphosphonate treatment in cancer patients. Wien Klinische Wochenschr. 2006;118:473–8.

    CAS  Google Scholar 

  11. 11.

    Otto S, Pautke C, Van den Wyngaert T, Niepel D, Schiodt M. Medication-related osteonecrosis of the jaw: prevention, diagnosis and management in patients with cancer and bone metastases. Cancer Treat Rev. 2018;69:177–87.

    PubMed  Google Scholar 

  12. 12.

    Amaral FGD, Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Arch Endocrinol Metab. 2018;62:472–9.

    PubMed  Google Scholar 

  13. 13.

    Slominski AT, Hardeland R, Zmijewski MA, Slominski RM, Reiter RJ, Paus R. Melatonin: a cutaneous perspective on its production, metabolism, and functions. J Invest Dermatol. 2018;138:490–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Wang B, Wen H, Smith W, Hao D, He B, Kong L. Regulation effects of melatonin on bone marrow mesenchymal stem cell differentiation. J Cell Physiol. 2019;234:1008–15.

    CAS  PubMed  Google Scholar 

  15. 15.

    Golan K, Kumari A, Kollet O, Khatib-Massalha E, Subramaniam MD, Ferreira ZS, et al. Daily onset of light and darkness differentially controls hematopoietic stem cell differentiation and maintenance. Cell Stem Cell. 2018;23:572–85 e577.

    CAS  PubMed  Google Scholar 

  16. 16.

    Golan K, Kollet O, Markus RP, Lapidot T. Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: the role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles. Exp Hematol. 2019;78:1–10.

    CAS  PubMed  Google Scholar 

  17. 17.

    Cordoba-Moreno MO, de Souza EDS, Quiles CL, Dos Santos-Silva D, Kinker GS, Muxel SM, et al. Rhythmic expression of the melatonergic biosynthetic pathway and its differential modulation in vitro by LPS and IL10 in bone marrow and spleen. Sci Rep. 2020;10:4799.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Markus RP, Fernandes PA, Kinker GS, da Silveira Cruz-Machado S, Marcola M. Immune-pineal axis – acute inflammatory responses coordinate melatonin synthesis by pinealocytes and phagocytes. Br J Pharm. 2018;175:3239–50.

    CAS  Google Scholar 

  19. 19.

    Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, et al. Melatonin: pharmacology, functions and therapeutic benefits. Curr Neuropharmacol. 2017;15:434–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Arendt J. Melatonin and human rhythms. Chronobiol Int. 2006;23:21–37.

    CAS  PubMed  Google Scholar 

  21. 21.

    Anderson G, Rodriguez M. Multiple sclerosis: the role of melatonin and N-acetylserotonin. Mult Scler Relat Disord. 2015;4:112–23.

    PubMed  Google Scholar 

  22. 22.

    Jahanban-Esfahlan R, Mehrzadi S, Reiter RJ, Seidi K, Majidinia M, Baghi HB, et al. Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes. Br J Pharm. 2018;175:3230–8.

    CAS  Google Scholar 

  23. 23.

    Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, et al. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8:39896–921.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Lv JW, Zheng ZQ, Wang ZX, Zhou GQ, Chen L, Mao YP, et al. Pan-cancer genomic analyses reveal prognostic and immunogenic features of the tumor melatonergic microenvironment across 14 solid cancer types. J Pineal Res. 2019;66:e12557.

    PubMed  Google Scholar 

  25. 25.

    Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 melatonin receptors: a therapeutic perspective. Annu Rev Pharmacol Toxicol. 2016;56:361–83.

    CAS  PubMed  Google Scholar 

  26. 26.

    Leaw B, Nair S, Lim R, Thornton C, Mallard C, Hagberg H. Mitochondria, bioenergetics and excitotoxicity: new therapeutic targets in perinatal brain injury. Front Cell Neurosci. 2017;11:199.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Boafo A, Greenham S, Alenezi S, Robillard R, Pajer K, Tavakoli P, et al. Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician’s perspective. Nat Sci Sleep. 2019;11:1–10.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys. 2008;473:201–9.

    CAS  PubMed  Google Scholar 

  29. 29.

    Roth JA, Kim BG, Lin WL, Cho MI. Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem. 1999;274:22041–7.

    CAS  PubMed  Google Scholar 

  30. 30.

    Kim HJ, Kim HJ, Bae MK, Kim YD. Suppression of osteoclastogenesis by melatonin: a melatonin receptor-independent action. Int J Mol Sci. 2017;18:1142.

    PubMed Central  Google Scholar 

  31. 31.

    Koyama H, Nakade O, Takada Y, Kaku T, Lau KH. Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res: Off J Am Soc Bone Miner Res. 2002;17:1219–29.

    CAS  Google Scholar 

  32. 32.

    Lopez-Canul M, Min SH, Posa L, De Gregorio D, Bedini A, Spadoni G, et al. Melatonin MT1 and MT2 receptors exhibit distinct effects in the modulation of body temperature across the light/dark cycle. Int J Mol Sci. 2019;20:2452.

    PubMed Central  Google Scholar 

  33. 33.

    Watkins LR, Orlandi C, Orphan G. Protein coupled receptors in affective disorders. Genes. 2020;11:694.

    PubMed Central  Google Scholar 

  34. 34.

    Chao CC, Chen PC, Chiou PC, Hsu CJ, Liu PI, Yang YC, et al. Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to Twist. Clin Sci. 2019;133:709–22.

    CAS  Google Scholar 

  35. 35.

    Bi H, Chen X, Gao S, Yu X, Xiao J, Zhang B, et al. Key triggers of osteoclast-related diseases and available strategies for targeted therapies: a review. Front Med. 2017;4:234.

    Google Scholar 

  36. 36.

    Shupp AB, Kolb AD, Mukhopadhyay D, Bussard KM. Cancer metastases to bone: concepts, mechanisms, and interactions with bone osteoblasts. Cancers. 2018;10:182.

    PubMed Central  Google Scholar 

  37. 37.

    Kim JH, Kim N. Signaling pathways in osteoclast differentiation. Chonnam Med J. 2016;52:12–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Guise TA, Chirgwin JM. Transforming growth factor-beta in osteolytic breast cancer bone metastases. Clin Orthop Relat Res. 2003;(415 Suppl):S32–8.

    Google Scholar 

  39. 39.

    Fowler TW, Kamalakar A, Akel NS, Kurten RC, Suva LJ, Gaddy D. Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures. J Cell Sci. 2015;128:683–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    van Dam PA, Verhoeven Y, Jacobs J, Wouters A, Tjalma W, Lardon F, et al. RANK-RANKL signaling in cancer of the uterine cervix: a review. Int J Mol Sci. 2019;20:2183.

    PubMed Central  Google Scholar 

  41. 41.

    Nakashima T, Kobayashi Y, Yamasaki S, Kawakami A, Eguchi K, Sasaki H, et al. Protein expression and functional difference of membrane-bound and soluble receptor activator of NF-kappaB ligand: modulation of the expression by osteotropic factors and cytokines. Biochem Biophys Res Commun. 2000;275:768–75.

    CAS  PubMed  Google Scholar 

  42. 42.

    Watanabe M, Kobayashi Y, Takahashi N, Kiguchi K, Ishizuka B. Expression of melatonin receptor (MT1) and interaction between melatonin and estrogen in endometrial cancer cell line. J Obstet Gynaecol Res. 2008;34:567–73.

    CAS  PubMed  Google Scholar 

  43. 43.

    Cutando A, Lopez-Valverde A, Dev J, Gimenez JL, Carcia IA, Ded RG. Action of melatonin on squamous cell carcinoma and other tumors of the oral cavity (Review). Oncol Lett. 2014;7:923–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Pandi-Perumal SR, BaHammam AS, Brown GM, Spence DW, Bharti VK, Kaur C, et al. Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes. Neurotox Res. 2013;23:267–300.

    CAS  PubMed  Google Scholar 

  45. 45.

    Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:6243s–9s.

    Google Scholar 

  46. 46.

    Maria S, Samsonraj RM, Munmun F, Glas J, Silvestros M, Kotlarczyk MP, et al. Biological effects of melatonin on osteoblast/osteoclast cocultures, bone, and quality of life: implications of a role for MT2 melatonin receptors, MEK1/2, and MEK5 in melatonin-mediated osteoblastogenesis. J Pineal Res. 2018;64: https://doi.org/10.1111/jpi.12465.

  47. 47.

    Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Prim. 2018;4:18002.

    Google Scholar 

  48. 48.

    Bang J, Chang HW, Jung HR, Cho CH, Hur JA, Lee SI, et al. Melatonin attenuates clock gene cryptochrome1, which may aggravate mouse anti-type II collagen antibody-induced arthritis. Rheumatol Int. 2012;32:379–85.

    CAS  PubMed  Google Scholar 

  49. 49.

    Chen Q, Wei W. Effects and mechanisms of melatonin on inflammatory and immune responses of adjuvant arthritis rat. Int Immunopharmacol. 2002;2:1443–9.

    CAS  PubMed  Google Scholar 

  50. 50.

    Huang CC, Chiou CH, Liu SC, Hu SL, Su CM, Tsai CH, et al. Melatonin attenuates TNF-alpha and IL-1beta expression in synovial fibroblasts and diminishes cartilage degradation: implications for the treatment of rheumatoid arthritis. J Pineal Res. 2019;66:e12560.

    PubMed  Google Scholar 

  51. 51.

    Ayoub MA, Levoye A, Delagrange P, Jockers R. Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers. Mol Pharmacol. 2004;66:312–21.

    CAS  PubMed  Google Scholar 

  52. 52.

    Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol. 2012;351:152–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Jung B, Ahmad N. Melatonin in cancer management: progress and promise. Cancer Res. 2006;66:9789–93.

    CAS  PubMed  Google Scholar 

  54. 54.

    Slominski AT, Zmijewski MA, Semak I, Kim TK, Janjetovic Z, Slominski RM, et al. Melatonin, mitochondria, and the skin. Cell Mol Life Sci. 2017;74:3913–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Yang YC, Chiou PC, Chen PC, Liu PY, Huang WC, Chao CC, et al. Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, beta-catenin, and twist pathways. Environ Toxicol. 2019;34:203–9.

    CAS  PubMed  Google Scholar 

  56. 56.

    Kim TK, Kleszczynski K, Janjetovic Z, Sweatman T, Lin Z, Li W, et al. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J: Off Publ Federation Am Soc Exp Biol. 2013;27:2742–55.

    CAS  Google Scholar 

  57. 57.

    Slominski AT, Semak I, Fischer TW, Kim TK, Kleszczynski K, Hardeland R, et al. Metabolism of melatonin in the skin: why is it important? Exp Dermatol. 2017;26:563–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Leja-Szpak A, Nawrot-Porabka K, Goralska M, Jastrzebska M, Link-Lenczowski P, Bonior J, et al. Melatonin and its metabolite N1-acetyl-N2-formyl-5-methoxykynuramine (afmk) enhance chemosensitivity to gemcitabine in pancreatic carcinoma cells (PANC-1). Pharmacol Rep. 2018;70:1079–88.

    CAS  PubMed  Google Scholar 

  59. 59.

    Lissoni P, Barni S, Meregalli S, Fossati V, Cazzaniga M, Esposti D, et al. Modulation of cancer endocrine therapy by melatonin: a phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. Br J Cancer. 1995;71:854–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Lissoni P, Meregalli S, Fossati V, Paolorossi F, Barni S, Tancini G, et al. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori. 1994;80:464–7.

    CAS  PubMed  Google Scholar 

  61. 61.

    Wang Y, Wang P, Zheng X, Du X. Therapeutic strategies of melatonin in cancer patients: a systematic review and meta-analysis. Onco Targets Ther. 2018;11:7895–908.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Menendez-Menendez J, Martinez-Campa C. Melatonin: an anti-tumor agent in hormone-dependent cancers. Int J Endocrinol. 2018;2018:3271948.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Palmer ACS, Zortea M, Souza A, Santos V, Biazus JV, Torres ILS, et al. Clinical impact of melatonin on breast cancer patients undergoing chemotherapy; effects on cognition, sleep and depressive symptoms: a randomized, double-blind, placebo-controlled trial. PLoS ONE. 2020;15:e0231379.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, et al. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012;11:293–303.

    CAS  PubMed  Google Scholar 

  65. 65.

    Farach-Carson MC, Lin SH, Nalty T, Satcher RL. Sex differences and bone metastases of breast, lung, and prostate cancers: do bone homing cancers favor feminized bone marrow? Front Oncol. 2017;7:163.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97:59–69.

    CAS  PubMed  Google Scholar 

  67. 67.

    Kozlow W, Guise TA. Breast cancer metastasis to bone: mechanisms of osteolysis and implications for therapy. J Mammary Gland Biol Neoplasia. 2005;10:169–80.

    PubMed  Google Scholar 

  68. 68.

    Rouach V, Goldshtein I, Wolf I, Catane R, Chodick G, Iton A, et al. Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer. J Bone Oncol. 2018;12:91–5.

    PubMed  PubMed Central  Google Scholar 

  69. 69.

    Dauchy RT, Xiang S, Mao L, Brimer S, Wren MA, Yuan L, et al. Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer. Cancer Res. 2014;74:4099–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Hall CL, Bafico A, Dai J, Aaronson SA, Keller ET. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005;65:7554–60.

    CAS  PubMed  Google Scholar 

  71. 71.

    Guise TA, Mohammad KS, Clines G, Stebbins EG, Wong DH, Higgins LS, et al. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res: Off J Am Assoc Cancer Res. 2006;12:6213s–6s.

    CAS  Google Scholar 

  72. 72.

    Han Y, Kim YM, Kim HS, Lee KY. Melatonin promotes osteoblast differentiation by regulating Osterix protein stability and expression. Sci Rep. 2017;7:5716.

    PubMed  PubMed Central  Google Scholar 

  73. 73.

    Meng X, Zhu Y, Tao L, Zhao S, Qiu S. miR-590-3p mediates melatonin-induced cell apoptosis by targeting septin 7 in the human osteoblast cell line hFOB 1.19. Mol Med Rep. 2018;17:7202–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Liu JF, Chen CY, Chen HT, Chang CS, Tang CH. BL-038, a Benzofuran derivative, induces cell apoptosis in human chondrosarcoma cells through reactive oxygen species/mitochondrial dysfunction and the caspases dependent pathway. Int J Mol Sci. 2016;17:1491.

    PubMed Central  Google Scholar 

  75. 75.

    Lee HP, Wang SW, Wu YC, Tsai CH, Tsai FJ, Chung JG, et al. Glucocerebroside reduces endothelial progenitor cell-induced angiogenesis. Food Agr Immunol. 2019;30:1033–45.

    CAS  Google Scholar 

  76. 76.

    Lee HP, Chen PC, Wang SW, Fong YC, Tsai CH, Tsai FJ, et al. Plumbagin suppresses endothelial progenitor cell-related angiogenesis in vitro and in vivo. J Funct Foods. 2019;52:537–44.

    CAS  Google Scholar 

  77. 77.

    Lee HP, Wang SW, Wu YC, Lin LW, Tsai FJ, Yang JS, et al. Soya-cerebroside inhibits VEGF-facilitated angiogenesis in endothelial progenitor cells. Food Agr Immunol. 2020;31:193–204.

    CAS  Google Scholar 

  78. 78.

    Wu MH, Lo JF, Kuo CH, Lin JA, Lin YM, Chen LM, et al. Endothelin-1 promotes MMP-13 production and migration in human chondrosarcoma cells through FAK/PI3K/Akt/mTOR pathways. J Cell Physiol. 2012;227:3016–26.

    CAS  PubMed  Google Scholar 

  79. 79.

    Wang M, Chao CC, Chen PC, Liu PI, Yang YC, Su CM, et al. Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis. Biochem Pharmacol. 2019;166:23–32.

    CAS  PubMed  Google Scholar 

  80. 80.

    Chuang JY, Chang AC, Chiang IP, Tsai MH, Tang CH. Apoptosis signal-regulating kinase 1 is involved in WISP-1-promoted cell motility in human oral squamous cell carcinoma cells. PloS ONE. 2013;8:e78022.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Chen PC, Cheng HC, Tang CH. CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway. Carcinogenesis. 2013;34:1669–79.

    CAS  PubMed  Google Scholar 

  82. 82.

    Chang AC, Chen PC, Lin YF, Su CM, Liu JF, Lin TH, et al. Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin alpha4beta1 system. Cancer Lett. 2018;426:47–56.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Iona J. MacDonald from China Medical University for her English language revision of this paper.

Funding

This study was supported by grants from Taiwan’s Ministry of Science and Technology (MOST 108-2320-B-039-026-, MOST 109-2320-B-341-002-), China Medical University Hospital (DMR-110-102), Shin Kong Wu Ho-Su Memorial Hospital (2020SKHBND001), China Medical University under the Higher Education Sprout Project, Ministry of Education, Taiwan (CMRC-CHM-3-1), Asia University Hospital (10951002) and Chung Shan Medical University Hospital, Taiwan (CSH-2020-E-001-Y3).

Author information

Affiliations

Authors

Contributions

Conceptualization, P-CC and C-HTang; data curation, A-CC and J-LL; formal analysis, P-IL and J-LL; investigation, P-IL and A-CC; methodology, J-LL; project administration, P-IL and A-CC; resources, T-HL and C-HTsai; software, A-CC and P-CC; supervision, W-CH, S-FY, and C-HTang; writing—original draft, P-IL and A-CC; writing—review and editing, S-FY and C-HTang.

Corresponding authors

Correspondence to Shun-Fa Yang or Chih-Hsin Tang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Verify currency and authenticity via CrossMark

Cite this article

Liu, PI., Chang, AC., Lai, JL. et al. Melatonin interrupts osteoclast functioning and suppresses tumor-secreted RANKL expression: implications for bone metastases. Oncogene 40, 1503–1515 (2021). https://doi.org/10.1038/s41388-020-01613-4

Download citation

Search

Quick links