Zoledronic acid inhibits the bone metastasis of breast cancer by repressing exosome-loaded DKK1

Authors

DOI:

https://doi.org/10.3329/bjp.v17i3.61292

Keywords:

Bone metastasis, Breast cancer, Exosomes, Osteoclast, Zolendronic

Abstract

This study is designed to investigate the mechanism underlying zoledronic acid for the bone metastasis of breast cancer. Dickkopf 1 (DKK1) was both expressed in breast cancer cells and exosomes isolated from breast cancer cells. The expression of DKK1 was synchronously inhibited in breast cancer cells and exosomes with zoledronic acid or transfecting with cDNA3.1-DKK1. The proliferation and migration of MDA-MB-453 cells were greatly repressed and the differentiation and maturity of osteoclasts were dramatically repressed by exosomes derived from zoledronic acid-treated MDA-MB-453 cells. In the co-cultural system of RAW264.7 cells and MDA-MB-453 cells, the proliferation and migration of MDA-MB-453 cells were facilitated by exosomes derived from MDA-MB-453 cells. Lastly, the EMT progression and TGF-β signaling were significantly blocked by exosomes derived from zoledronic acid-treated MDA-MB-453 cells. Zoledronic acid suppressed the bone metastasis of breast cancer by inhibiting the exosomes loaded with DKK1.

Downloads

Download data is not yet available.
Abstract
36
Download
28

References

Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res. 2013; 92: 860-67.

Bryant R, Pawlowski T, Catto JW, Marsden G, Vessella RL, Rhees B, Kuslich C, Visakorpi T, Hamdy FC. Changes in circulating microRNA levels associated with prostate cancer. Br J Cancer. 2012; 106: 768-74.

Chen XL. Lycorine inhibits MDA-MB-231 breast cancer cells proliferation, migration and invasion is associated with Wnt/β-catenin signaling. Bangladesh J Pharmacol. 2018; 13: 192-95.

Chen Y, Whetstone HC, Youn A, Nadesan P, Chow EC, Lin AC, Alman BA. Beta-catenin signaling pathway is crucial for bone morphogenetic protein 2 to induce new bone formation. J Biol Chem. 2007; 282: 526-33.

Chicón-Bosch M, Tirado OM. Exosomes in bone sarcomas: Key players in metastasis. Cells 2020; 9: 241.

Clezardin P. Therapeutic targets for bone metastases in breast cancer. Breast Cancer Res. 2011; 13: 207.

Roodman GD, Silbermann R. Mechanisms of osteolytic and osteoblastic skeletal lesions. Bonekey Rep. 2015; 4: 753.

Ell B, Kang Y. SnapShot: Bone metastasis. Cell 2012; 151: 690-90.

Fujita KI, Janz S. Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF. Mol Cancer. 2007; 6: 71.

Glass II DA, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, Taketo MM, Long F, McMahon AP, Lang RA, Karsenty G. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005; 8: 751-64.

Göbel A, Browne AJ, Thiele S, Rauner M, Hofbauer LC, Rachner TD. Potentiated suppression of Dickkopf-1 in breast cancer by combined administration of the mevalonate pathway inhibitors zoledronic acid and statins. Breast Cancer Res Treat. 2015; 154: 623-31.

Goldvaser H, Amir E. Role of bisphosphonates in breast cancer therapy. Curr Treat Options Oncol. 2019, 20: 1-17.

Guo HYB, Liu XX, Zhu XY, Yu Z. Mulberrofuran G inhibits proliferation and migration by inactivating JAK2/STAT3 signaling in lung cancer cells. Bangladesh J Pharmacol. 2021; 16: 134-40.

Gürbüz P, Düzova H, Yildiz A, Çakan P, Kaya GB, Bağ HGG, Durhan M, Gül CC, Taşlidere AÇ. Effects of noopept on cognitive functions and pubertal process in rats with diabetes. Life Sci. 2019; 233: 116698.

Holmen SL, Zylstra CR, Mukherjee A, Sigler RE, Faugere MC, Bouxsein ML, Deng L, Clemens TL, Williams BO. Essential role of beta-catenin in postnatal bone acquisition. J Biol Chem. 2005; 280: 21162-68.

Huang Y, Liu L, Liu A. Dickkopf-1: Current knowledge and related diseases. Life Sci. 2018; 209: 249-54.

Kahlert C, Kalluri R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J Mol Med (Berl). 2013; 91: 431-37.

Kang Y. Dissecting tumor-stromal interactions in breast cancer bone metastasis. Endocrinol Metab (Seoul). 2016; 31: 206-12.

Khosla S. Minireview: The OPG/RANKL/RANK system. Endocrinology 2001; 142: 5050-55.

Krempien R, Niethammer A, Harms W, Debus J. Bisphosphonates and bone metastases: Current status and future directions. Expert Rev Anticancer Ther. 2005; 5: 295-305.

Liang Z, Wu H, Reddy S, Zhu A, Wang S, Blevins D, Yoon Y, Zhang Y, Shim H. Blockade of invasion and metastasis of breast cancer cells via targeting CXCR4 with an artificial microRNA. Biochem Biophys Res Commun. 2007; 363: 542-546.

Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001; 411: 375-79.

Liu S, Wang L, Zhang R. Corylin suppresses metastasis of breast cancer cells by modulating miR-34c/LINC00963 target. Libyan J Med. 2021; 16: 1883224.

Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, Vargo-Gogola TC, Begtrup JL, Peterson TE, Fingleton B, Shirai T. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell. 2005; 7: 485-96.

Meng Z, Zhang R, Wang Y, Zhu G, Jin T, Li C, Zhang S. miR-200c/PAI-2 promotes the progression of triple negative breast cancer via M1/M2 polarization induction of macrophage. Int Immunopharmacol. 2020, 81: 106028.

Miyamoto T. Regulators of osteoclast differentiation and cell-cell fusion. Keio J Med. 2011; 60: 101-05.

Mundy GR. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002; 2: 584-93.

Ohno SI, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, Fujita K, Mizutani T, Ohgi T, Ochiya T, Gotoh N, Kuroda M. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013; 21: 185-91.

Polyzos SA, Anastasilakis AD, Efstathiadou Z, Kita M, Litsas I, Avramidis A, Arsos G, Moralidis E, Gerou S, Pavlidou V, Papatheodorou A. The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with Paget's disease of bone. Horm Metab Res. 2009; 41: 846-50.

Qiang YW, Chen Y, Brown N, Hu B, Epstein J, Barlogie B, Shaughnessy Jr JD. Characterization of Wnt/beta-catenin signalling in osteoclasts in multiple myeloma. Br J Haematol. 2010; 148: 726-38.

Rabinowits G, Gerçel-Taylor C, Day JM, Taylor DD, Kloecker GH. Exosomal microRNA: A diagnostic marker for lung cancer. Clin Lung Cancer. 2009; 10: 42-46.

Ren D, Yang Q, Dai Y, Guo W, Du H, Song L, Peng X. Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-kappaB signaling pathway. Mol Cancer. 2017; 16: 117.

Song C, Yang X, Lei Y, Zhang Z, Smith W, Yan J, Kong L. Evaluation of efficacy on RANKL induced osteoclast from RAW264. 7 cells. J Cell Physiol. 2019; 234: 11969-75.

Spencer GJ, Utting JC, Etheridge SL, Arnett TR, Genever PG. Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. J Cell Sci. 2006; 119: 1283-96.

Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: A fatal attraction. Nat Rev Cancer. 2011; 11: 411-25.

Yan W, Ma X, Zhao X, Zhang S. Baicalein induces apoptosis and autophagy of breast cancer cells via inhibiting PI3K/AKT pathway in vivo and vitro. Drug Des Devel Ther. 2018, 12: 3961.

Yang SS, Ma S, Dou H, Liu F, Zhang SY, Jiang C, Xiao M, Huang YX. Breast cancer-derived exosomes regulate cell invasion and metastasis in breast cancer via miR-146a to activate cancer associated fibroblasts in tumor microenvironment. Exp Cell Res. 2020, 391: 111983.

Yuan X, Qian N, Ling S, Li Y, Sun W, Li J, Du R, Zhong G, Liu C, Yu G, Cao D. Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells. Theranostics 2021; 11: 1429-45.

Zhang X, Yuan X, Shi H, Wu L, Qian H, Xu W. Exosomes in cancer: Small particle, big player. J Hematol Oncol. 2015; 8: 83.

Zhou Y, Wang L, Lin H, Wang Y, Hou K. Bufalin inhibits the growth and epithelial to mesenchymal transition of human gastric cancer cells via modulation of MEK/ERK pathway. Bangladesh J Pharmacol. 2021, 16: 27-33.

Downloads

Published

2022-09-07

How to Cite

Song, B. B., M. Y. . Xu, X. F. Xu, . X. Li, and M. Chen. “Zoledronic Acid Inhibits the Bone Metastasis of Breast Cancer by Repressing Exosome-Loaded DKK1”. Bangladesh Journal of Pharmacology, vol. 17, no. 3, Sept. 2022, pp. 92-101, doi:10.3329/bjp.v17i3.61292.

Issue

Vol. 17 No. 3 (2022)

Section

Research Articles

License

Copyright (c) 2022 Bin Bin Song, Mao Yi Xu, Xiao Fang Xu, Xia Li, Ming Chen

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

  1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
  2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
  3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).