Melatonin impedes prostate cancer metastasis by suppressing MMP-13 expression
Shih-Wei Wang
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
Search for more papers by this authorHuai-Ching Tai
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan
Search for more papers by this authorChih-Hsin Tang
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
Search for more papers by this authorLiang-Wei Lin
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
Search for more papers by this authorTien-Huang Lin
Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan
School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
Search for more papers by this authorAn-Chen Chang
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
Search for more papers by this authorPo-Chun Chen
Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
Search for more papers by this authorYi-Hsuan Chen
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
Department of Urology, MacKay Memorial Hospital, Taipei, Taiwan
Search for more papers by this authorPo-Chuan Wang
Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan
Search for more papers by this authorYu-Wei Lai
Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan
Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan
Search for more papers by this authorCorresponding Author
Shiou-Sheng Chen
Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan
Division of Urology, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan
Commission for General Education, College of Applied Science, National Taiwan University of Science and Technology, Taipei, Taiwan
Correspondence Shiou-Sheng Chen, Department of Urology, National Yang-Ming University School of Medicine, Commission for General Education, College of Applied Science, National Taiwan University of Science and Technology, Department of Urology, Taipei City Hospital Zhongxiao Branch, No. 87, Tongde Rd., Nangang Dist., Taipei 115, Taiwan.
Email: [email protected]
Search for more papers by this authorShih-Wei Wang
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
Search for more papers by this authorHuai-Ching Tai
School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan
Search for more papers by this authorChih-Hsin Tang
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
Search for more papers by this authorLiang-Wei Lin
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
Search for more papers by this authorTien-Huang Lin
Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan
School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan
Search for more papers by this authorAn-Chen Chang
Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
Search for more papers by this authorPo-Chun Chen
Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
Search for more papers by this authorYi-Hsuan Chen
Department of Medicine, MacKay Medical College, New Taipei City, Taiwan
Department of Urology, MacKay Memorial Hospital, Taipei, Taiwan
Search for more papers by this authorPo-Chuan Wang
Department of Gastroenterology, Hsinchu MacKay Memorial Hospital, Hsinchu City, Taiwan
Search for more papers by this authorYu-Wei Lai
Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan
Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan
Search for more papers by this authorCorresponding Author
Shiou-Sheng Chen
Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan
Division of Urology, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan
Commission for General Education, College of Applied Science, National Taiwan University of Science and Technology, Taipei, Taiwan
Correspondence Shiou-Sheng Chen, Department of Urology, National Yang-Ming University School of Medicine, Commission for General Education, College of Applied Science, National Taiwan University of Science and Technology, Department of Urology, Taipei City Hospital Zhongxiao Branch, No. 87, Tongde Rd., Nangang Dist., Taipei 115, Taiwan.
Email: [email protected]
Search for more papers by this authorShih-Wei Wang and Chih-Hsin Tang contributed equally to this study.
Abstract
Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP-13) expression are higher in prostate cancer patients than in healthy cancer-free individuals. Mechanistic investigations revealed that melatonin inhibits MMP-13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c-Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP-13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| jcp30150-sup-0001-Supplementary_data.pdf151 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- Amar, S., Smith, L., & Fields, G. B. (2017). Matrix metalloproteinase collagenolysis in health and disease. Biochimica et Biophysica Acta, Molecular Cell Research, 1864(11 Pt A), 1940–1951. https://doi.org/10.1016/j.bbamcr.2017.04.015
- Arendt, J. (2006). Melatonin and human rhythms. Chronobiology International, 23(1-2), 21–37. https://doi.org/10.1080/07420520500464361
- Boafo, A., Greenham, S., Alenezi, S., Robillard, R., Pajer, K., Tavakoli, P., & De Koninck, O. (2019). Could long-term administration of melatonin to prepubertal children affect timing of puberty? A clinician's perspective. Nature and Science of Sleep, 11, 1–10. https://doi.org/10.2147/Nss.S181365
- Calvo, J. R., Gonzalez-Yanes, C., & Maldonado, M. D. (2013). The role of melatonin in the cells of the innate immunity: A review. Journal of Pineal Research, 55(2), 103–120. https://doi.org/10.1111/jpi.12075
- Chao, C. C., Chen, P. C., Chiou, P. C., Hsu, C. J., Liu, P. I., Yang, Y. C., Reiter, R. J., Yang, S. F., & Tang, C. H. (2019). Melatonin suppresses lung cancer metastasis by inhibition of epithelial-mesenchymal transition through targeting to Twist. Clinical Science (Lond), 133(5), 709–722. https://doi.org/10.1042/CS20180945
- Chen, C. Y., Su, C. M., Hsu, C. J., Huang, C. C., Wang, S. W., Liu, S. C., Chen, W. C., Fuh, L. J., & Tang, C. H. (2017). CCN1 promotes VEGF production in osteoblasts and induces endothelial progenitor cell angiogenesis by inhibiting mir-126 expression in rheumatoid arthritis. Journal of Bone and Mineral Research, 32(1), 34–45. https://doi.org/10.1002/jbmr.2926
- Chen, P. C., Tang, C. H., Lin, L. W., Tsai, C. H., Chu, C. Y., Lin, T. H., & Huang, Y. L. (2017). Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression. Journal of Hematology & Oncology, 10, 33. https://doi.org/10.1186/s13045-017-0390-6
- Cutando, A., Lopez-Valverde, A., Arias-Santiago, S., De Vicente, J., & De Diego, R. G. (2012). Role of melatonin in cancer treatment. Anticancer Research, 32(7), 2747–2753.
- Deng, X., He, G., Liu, J., Luo, F., Peng, X., Tang, S., Gao, Z., Lin, Q., Keller, J. M., Yang, T., & Keller, E. T. (2014). Recent advances in bone-targeted therapies of metastatic prostate cancer. Cancer Treatment Reviews, 40(6), 730–738. https://doi.org/10.1016/j.ctrv.2014.04.003
- Dubocovich, M. L., Delagrange, P., Krause, D. N., Sugden, D., Cardinali, D. P., & Olcese, J. (2010). International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacological Reviews, 62(3), 343–380.
- Grant, S. G., Melan, M. A., Latimer, J. J., & Witt-Enderby, P. A. (2009). Melatonin and breast cancer: Cellular mechanisms, clinical studies and future perspectives. Expert Reviews in Molecular Medicine, 11, e5. https://doi.org/10.1017/S1462399409000982
- Hu, S. L., Huang, C. C., Tseng, T. T., Liu, S. C., Tsai, C. H., Fong, Y. C., & Tang, C. H. (2020). S1P facilitates IL-1beta production in osteoblasts via the JAK and STAT3 signaling pathways. Environmental Toxicology, 35(9), 991–997. https://doi.org/10.1002/tox.22935
- Huang, C. C., Chiou, C. H., Liu, S. C., Hu, S. L., Su, C. M., Tsai, C. H., & Tang, C. H. (2019). Melatonin attenuates TNF-alpha and IL-1beta expression in synovial fibroblasts and diminishes cartilage degradation: Implications for the treatment of rheumatoid arthritis. Journal of Pineal Research, 66(3), e12560. https://doi.org/10.1111/jpi.12560
- Lee, H. P., Chen, P. C., Wang, S. W., Fong, Y. C., Tsai, C. H., Tsai, F. J., Chung, J. G., Huang, C. Y., Yang, J. S., Hsu, Y. M., Li, T. M., & Tang, C. H. (2019). Plumbagin suppresses endothelial progenitor cell-related angiogenesis in vitro and in vivo. Journal of Functional Foods, 52, 537–544. https://doi.org/10.1016/j.jff.2018.11.040
- Lee, H.-P., Wang, S.-W., Wu, Y.-C., Tsai, C.-H., Tsai, F.-J., Chung, J.-G., Huang, C. Y., Yang, J. S., Hsu, Y. M., Yin, M. C., Li, T. M., & Tang, C. H. (2019). Glucocerebroside reduces endothelial progenitor cell-induced angiogenesis. Food and Agricultural Immunology, 30(1), 1033–1045. https://doi.org/10.1080/09540105.2019.1660623
- Lee, H.-P., Wu, Y.-C., Chen, B.-C., Liu, S.-C., Li, T.-M., Huang, W.-C., Hsu, C. J., & Tang, C. H. (2020). Soya-cerebroside reduces interleukin production in human rheumatoid arthritis synovial fibroblasts by inhibiting the ERK, NF-κB and AP-1 signalling pathways. Food and agricultural immunology, 31(1), 740–750. https://doi.org/10.1080/09540105.2020.1766426
- Lien, M. Y., Tsai, H. C., Chang, A. C., Tsai, M. H., Hua, C. H., Wang, S. W., & Tang, C. H. (2018). Chemokine CCL4 induces vascular endothelial growth factor C expression and lymphangiogenesis by miR-195-3p in oral squamous cell carcinoma. Frontiers in Immunology, 9, 412. https://doi.org/10.3389/fimmu.2018.00412
- Lin, C. C., Chen, K. B., Tsai, C. H., Tsai, F. J., Huang, C. Y., Tang, C. H., Yang, J. S., Hsu, Y. M., Peng, S. F., & Chung, J. G. (2019). Casticin inhibits human prostate cancer DU 145 cell migration and invasion via Ras/Akt/NF-kappaB signaling pathways. Journal of Food Biochemistry, 43(7), e12902. https://doi.org/10.1111/jfbc.12902
- Lin, C. Y., Wang, S. W., Chen, Y. L., Chou, W. Y., Lin, T. Y., Chen, W. C., Yang, C. Y., Liu, S. C., Hsieh, C. C., Fong, Y. C., Wang, P. C., & Tang, C. H. (2017). Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells. Cell Death & Disease, 8(8), e2964. https://doi.org/10.1038/cddis.2017.354
- Lissoni, P., Barni, S., Meregalli, S., Fossati, V., Cazzaniga, M., Esposti, D., & Tancini, G. (1995). Modulation of cancer endocrine therapy by melatonin: A phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone. British Journal of Cancer, 71(4), 854–856. https://doi.org/10.1038/bjc.1995.164
- Liu, J. F., Lee, C. W., Tsai, M. H., Tang, C. H., Chen, P. C., Lin, L. W., Lin, C. Y., Lu, C. H., Lin, Y. F., Yang, S. H., & Chao, C. C. (2018). Thrombospondin 2 promotes tumor metastasis by inducing matrix metalloproteinase-13 production in lung cancer cells. Biochemical Pharmacology, 155, 537–546. https://doi.org/10.1016/j.bcp.2018.07.024
- Liu, S. C., Tsai, C. H., Wu, T. Y., Tsai, C. H., Tsai, F. J., Chung, J. G., Huang, C. Y., Yang, J. S., Hsu, Y. M., Yin, M. C., Wu, Y. C., & Tang, C. H. (2019). Soya-cerebroside reduces IL-1 beta-induced MMP-1 production in chondrocytes and inhibits cartilage degradation: Implications for the treatment of osteoarthritis. Food and Agricultural Immunology, 30(1), 620–632. https://doi.org/10.1080/09540105.2019.1611745
- Liu, X., Tian, X. D., Liu, Y., Zhang, T., & Chen, L. (2016). Regulation of Twist in the metastasis of non-small cell lung cancer by miR-92b. European Review for Medical and Pharmacological Sciences, 20(19), 4003–4010.
- López-Canul, M., Min, S. H., Posa, L., De Gregorio, D., Bedini, A., Spadoni, G., Gobbi, G., & Comai, S. (2019). Melatonin MT1 and MT2 receptors exhibit distinct effects in the modulation of body temperature across the light/dark cycle. International Journal of Molecular Sciences, 20(10), 2452. https://doi.org/10.3390/ijms20102452
- Martin-Renedo, J., Mauriz, J. L., Jorquera, F., Ruiz-Andres, O., Gonzalez, P., & Gonzalez-Gallego, J. (2008). Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. Journal of Pineal Research, 45(4), 532–540. https://doi.org/10.1111/j.1600-079X.2008.00641.x
- Mediavilla, M. D., Sanchez-Barcelo, E. J., Tan, D. X., Manchester, L., & Reiter, R. J. (2010). Basic mechanisms involved in the anti-cancer effects of melatonin. Current Medicinal Chemistry, 17(36), 4462–4481.
- Mummidi, S., Das, N. A., Carpenter, A. J., Yoshida, T., Yariswamy, M., Mostany, R., Izadpanah, R., Higashi, Y., Sukhanov, S., Noda, M., Siebenlist, U., Rector, R. S., & Chandrasekar, B. (2019). RECK suppresses interleukin-17/TRAF3IP2-mediated MMP-13 activation and human aortic smooth muscle cell migration and proliferation. Journal of Cellular Physiology, 234(12), 22242–22259. https://doi.org/10.1002/jcp.28792
- Nabeshima, K., Inoue, T., Shimao, Y., & Sameshima, T. (2002). Matrix metalloproteinases in tumor invasion: Role for cell migration. Pathology International, 52(4), 255–264. https://doi.org/10.1046/j.1440-1827.2002.01343.x
- Pang, S. T., Flores-Morales, A., Skoog, L., Chuan, Y. C., Nordstedt, G., & Pousette, A. (2004). Regulation of matrix metalloproteinase 13 expression by androgen in prostate cancer. Oncology Reports, 11(6), 1187–1192.
- Phillips, R. M., Deek, M. P., Deweese, T. L., & Tran, P. T. (2019). Metastasis-directed therapy in prostate cancer. Why, when, and how? Oncology (Williston Park), 33(10.
- Reiter, R. J., Rosales-Corral, S., Tan, D. X., Jou, M. J., Galano, A., & Xu, B. (2017). Melatonin as a mitochondria-targeted antioxidant: One of evolution's best ideas. Cellular and Molecular Life Science, 74(21), 3863–3881. https://doi.org/10.1007/s00018-017-2609-7
- Reiter, R. J., Rosales-Corral, S. A., Tan, D. X., Acuna-Castroviejo, D., Qin, L., Yang, S. F., & Xu, K. (2017). Melatonin, a full service anti-cancer agent: Inhibition of initiation, progression and metastasis. International Journal of Molecular Sciences, 18(4), 843. https://doi.org/10.3390/ijms18040843
- Siegel, R. L., Miller, K. D., & Jemal, A. (2019). Cancer statistics, 2019. CA: A Cancer Journal for Clinicians, 69(1), 7–34. https://doi.org/10.3322/caac.21551
- Su, C. M., Tang, C. H., Chi, M. J., Lin, C. Y., Fong, Y. C., Liu, Y. C., Chen, W. C., & Wang, S. W. (2018). Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells. Biochemical Pharmacology, 154, 234–242. https://doi.org/10.1016/j.bcp.2018.05.001
- Su, S. C., Hsieh, M. J., Yang, W. E., Chung, W. H., Reiter, R. J., & Yang, S. F. (2017). Cancer metastasis: Mechanisms of inhibition by melatonin. Journal of Pineal Research, 62(1), e12370. https://doi.org/10.1111/jpi.12370
- Tan, D. X., Hardeland, R., Manchester, L. C., Korkmaz, A., Ma, S., Rosales-Corral, S., & Reiter, R. J. (2012). Functional roles of melatonin in plants, and perspectives in nutritional and agricultural science. Journal of Experimental Botany, 63(2), 577–597. https://doi.org/10.1093/jxb/err256
- Tang, C. H., Chen, C. F., Chen, W. M., & Fong, Y. C. (2011). IL-6 increases MMP-13 expression and motility in human chondrosarcoma cells. Journal of Biological Chemistry, 286(13), 11056–11066. https://doi.org/10.1074/jbc.M110.204081
- Tordjman, S., Chokron, S., Delorme, R., Charrier, A., Bellissant, E., Jaafari, N., & Fougerou, C. (2017). Melatonin: Pharmacology, functions and therapeutic benefits. Current Neuropharmacology, 15(3), 434–443. https://doi.org/10.2174/1570159X14666161228122115
- Tu, C. Y., Cheng, F. J., Chen, C. M., Wang, S. L., Hsiao, Y. C., Chen, C. H., Hsia, T. C., He, Y. H., Wang, B. W., Hsieh, I. S., Yeh, Y. L., Tang, C. H., Chen, Y. J., & Huang, W. C. (2018). Cigarette smoke enhances oncogene addiction to c-MET and desensitizes EGFR-expressing non-small cell lung cancer to EGFR TKIs. Molecular Oncology, 12(5), 705–723. https://doi.org/10.1002/1878-0261.12193
- Tzeng, H. E., Chen, J. C., Tsai, C. H., Kuo, C. C., Hsu, H. C., Hwang, W. L., Fong, Y. C., & Tang, C. H. (2011). CCN3 increases cell motility and MMP-13 expression in human chondrosarcoma through integrin-dependent pathway. Journal of Cellular Physiology, 226(12), 3181–3189. https://doi.org/10.1002/jcp.22672
- Wang, M., Chao, C. C., Chen, P. C., Liu, P. I., Yang, Y. C., Su, C. M., Huang, W. C., & Tang, C. H. (2019). Thrombospondin enhances RANKL-dependent osteoclastogenesis and facilitates lung cancer bone metastasis. Biochemical Pharmacology, 166, 23–32. https://doi.org/10.1016/j.bcp.2019.05.005
- Wu, D., Huang, P., Wang, L., Zhou, Y., Pan, H., & Qu, P. (2013). MicroRNA-143 inhibits cell migration and invasion by targeting matrix metalloproteinase 13 in prostate cancer. Molecular Medicine Reports, 8(2), 626–630. https://doi.org/10.3892/mmr.2013.1501
- Wu, T. J., Lin, C. Y., Tsai, C. H., Huang, Y. L., & Tang, C. H. (2018). Glucose suppresses IL-1-induced MMP-1 expression through the FAK, MEK, ERK, and AP-1 signaling pathways. Environmental Toxicology, 33(10), 1061–1068. https://doi.org/10.1002/tox.22618
- Xue, J., Chen, Z., Gu, X., Zhang, Y., & Zhang, W. (2016). MicroRNA-148a inhibits migration of breast cancer cells by targeting MMP-13. Tumour Biology, 37(2), 1581–1590. https://doi.org/10.1007/s13277-015-3926-9
- Yang, Y. C., Chiou, P. C., Chen, P. C., Liu, P. Y., Huang, W. C., Chao, C. C., & Tang, C. H. (2019). Melatonin reduces lung cancer stemness through inhibiting of PLC, ERK, p38, beta-catenin, and Twist pathways. Environmental Toxicology, 34(2), 203–209. https://doi.org/10.1002/tox.22674
- Zhao, X., Sun, B., Li, Y., Liu, Y., Zhang, D., Wang, X., Gu, Q., Zhao, J., Dong, X., Liu, Z., & Che, N. (2015). Dual effects of collagenase-3 on melanoma: Metastasis promotion and disruption of vasculogenic mimicry. Oncotarget, 6(11), 8890–8899. https://doi.org/10.18632/oncotarget.3189
