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Demethoxycucumin protects MDA-MB-231 cells induced bone destruction through JNK and ERK pathways inhibition

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Abstract

Bone is the most common late metastasis of breast cancer. Bone metastasis causes not only severe bone pain, but also bone-related diseases such as pathological fractures, which are closely related to osteoclasts. The effects of demethoxycurcumin (DMC) on osteoclast biology has not been investigated. In this study, we explored the effects of DMC on MDA-MB-231 cells, MCF-7 cells, and osteoclasts induced by RANKL in vitro, as well as the protective effect on bone destruction of tumor bone metastasis in vivo. DMC showed inhibitory effect on the migration and promotes the apoptosis of MDA-MB-231 and MCF-7 cells. At the same time, DMC inhibited osteoclast maturation and mature osteoclast bone resorption in a dose-dependent manner, and suppressed the expression of osteoclast marker genes TRAP, CTSK, MMP9, V-ATPase-d2 and DC-STAMP significantly. Biochemical data showed that DMC inhibited tumor cells and osteoclasts by inhibiting the early activation of ERK and JNK MAPK pathway. Consistent with the results in vitro, we confirmed that DMC protects bone destruction caused by tumor metastasis in vivo. In short, our study confirmed that DMC could be used as a potential drug for the treatment of tumor bone destruction.

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References

  1. Torre L et al (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108

    Article  PubMed  Google Scholar 

  2. Pattarawat P et al (2020) Formulation of a triple combination gemcitabine plus romidepsin + cisplatin regimen to efficaciously and safely control triple-negative breast cancer tumor development. Cancer ChemotherPharmacol 85(1):141–152

    CAS  Google Scholar 

  3. Kim S et al (2017) Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 18(10):1360–1372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ibrahim M et al (2015) Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis. Ann OncolOff J EurSoc Med Oncol 26(11):2205–2213

    Article  CAS  Google Scholar 

  5. Chen Y, Sosnoski D, Mastro A (2010) Breast cancer metastasis to the bone: mechanisms of bone loss. Breast Cancer Res BCR 12(6):215

    Article  CAS  PubMed  Google Scholar 

  6. Wood S, Westbrook J, Brown J (2014) Omic-profiling in breast cancer metastasis to bone: implications for mechanisms, biomarkers and treatment. Cancer Treat Rev 40(1):139–152

    Article  CAS  PubMed  Google Scholar 

  7. Quayle L, Ottewell P, Holen I (2015) Bone metastasis: molecular mechanisms implicated in tumour cell dormancy in breast and prostate cancer. Curr Cancer Drug Targets 15(6):469–480

    Article  CAS  PubMed  Google Scholar 

  8. Tanaka R et al (2016) Risk factors for developing skeletal-related events in breast cancer patients with bone metastases undergoing treatment with bone-modifying agents. Oncologist 21(4):508–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Niikura K (2007) Effect of a V-ATPase inhibitor, FR202126, in syngeneic mouse model of experimental bone metastasis. Cancer ChemotherPharmacol 60(4):555–562

    CAS  Google Scholar 

  10. Mundy G (2002) Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer 2(8):584–593

    Article  CAS  PubMed  Google Scholar 

  11. Guise T et al (2006) Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin Cancer Res Off J Am Assoc Cancer Res 12:6213s–6216s

    Article  CAS  Google Scholar 

  12. Yoneda T, Hiraga T (2005) Crosstalk between cancer cells and bone microenvironment in bone metastasis. Biochem Biophys Res Commun 328(3):679–687

    Article  CAS  Google Scholar 

  13. Karsenty G, Olson E (2016) Bone and muscle endocrine functions: unexpected paradigms of inter-organ communication. Cell 164(6):1248–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Currey J, Dean M, Shahar R (2017) Revisiting the links between bone remodelling and osteocytes: insights from across phyla. Biol Rev Camb Philos Soc 92(3):1702–1719

    Article  Google Scholar 

  15. Tibullo D et al (2020) Ixazomib improves bone remodeling and counteracts sonic hedgehog signaling inhibition mediated by myeloma cells. Cancers 12(2):323

    Article  CAS  PubMed Central  Google Scholar 

  16. Ell B et al (2013) Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell 24(4):542–556

    Article  CAS  PubMed  Google Scholar 

  17. Bennett C et al (2018) Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients. ActaNeuropathol 136(3):425–443

    CAS  Google Scholar 

  18. Min Y et al (2010) Tie2 signaling regulates osteoclastogenesis and osteolytic bone invasion of breast cancer. Can Res 70(7):2819–2828

    Article  CAS  Google Scholar 

  19. Kim B, Koh J (2019) Coupling factors involved in preserving bone balance. Cell Mol Life Sci CMLS 76(7):1243–1253

    Article  CAS  PubMed  Google Scholar 

  20. Yuan F et al (2018) Osteoclast-derived extracellular vesicles: novel regulators of osteoclastogenesis and osteoclast-osteoblasts communication in bone remodeling. Front Physiol 9:628

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cao X (2011) Targeting osteoclast-osteoblast communication. Nat Med 17(11):1344–1346

    Article  CAS  PubMed  Google Scholar 

  22. Teitelbaum S (2000) Bone resorption by osteoclasts. Science (New York, NY) 289(5484):1504–1508

    Article  CAS  Google Scholar 

  23. Jacome-Galarza C et al (2019) Developmental origin, functional maintenance and genetic rescue of osteoclasts. Nature 568(7753):541–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yahara Y et al (2020) Erythromyeloid progenitors give rise to a population of osteoclasts that contribute to bone homeostasis and repair. Nat Cell Biol 22(1):49–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mensah K, Ritchlin C, Schwarz E (2010) RANKL induces heterogeneous DC-STAMP(lo) and DC-STAMP(hi) osteoclast precursors of which the DC-STAMP(lo) precursors are the master fusogens. J Cell Physiol 223(1):76–83

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Boyce B (2013) Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res 92(10):860–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ikebuchi Y et al (2018) Coupling of bone resorption and formation by RANKL reverse signalling. Nature 561(7722):195–200

    Article  CAS  PubMed  Google Scholar 

  28. Jules J et al (2015) The IVVY motif and tumor necrosis factor receptor-associated factor (TRAF) sites in the cytoplasmic domain of the receptor activator of nuclear factor κB (RANK) cooperate to induce osteoclastogenesis. J BiolChem 290(39):23738–23750

    CAS  Google Scholar 

  29. Boyle W, Simonet W, Lacey D (2003) Osteoclast differentiation and activation. Nature 423(6937):337–342

    Article  CAS  PubMed  Google Scholar 

  30. Li X et al (2002) p38 MAPK-mediated signals are required for inducing osteoclast differentiation but not for osteoclast function. Endocrinology 143(8):3105–3113

    Article  CAS  PubMed  Google Scholar 

  31. Hatamipour M et al (2018) Demethoxycurcumin: a naturally occurring curcumin analogue with antitumor properties. J Cell Physiol 233(12):9247–9260

    Article  CAS  PubMed  Google Scholar 

  32. Hatamipour M et al (2019) Demethoxycurcumin: a naturally occurring curcumin analogue for treating non-cancerous diseases. J Cell Physiol 234(11):19320–19330

    Article  CAS  PubMed  Google Scholar 

  33. Arshad L et al (2017) An overview of structure–activity relationship studies of curcumin analogs as antioxidant and anti-inflammatory agents. Fut Med Chem 9(6):605–626

    Article  CAS  Google Scholar 

  34. Ramkumar M et al (2018) Demethoxycurcumin, a natural derivative of curcumin abrogates rotenone-induced dopamine depletion and motor deficits by its antioxidative and anti-inflammatory properties in Parkinsonian Rats. Pharmacog Mag 14(53):9–16

    Article  CAS  Google Scholar 

  35. Dos Santos P et al (2019) The nanoencapsulation of curcuminoids extracted from Curcuma longa L. and an evaluation of their cytotoxic, enzymatic, antioxidant and anti-inflammatory activities. Food Funct 10(2):573–582

    Article  PubMed  Google Scholar 

  36. Srirod S, Tewtrakul S (2019) Anti-inflammatory and wound healing effects of cream containing Curcuma mangga extract. J Ethnopharmacol 238:111828

    Article  CAS  PubMed  Google Scholar 

  37. Ahmed T, Gilani A (2014) Therapeutic potential of turmeric in Alzheimer’s disease: curcumin or curcuminoids? Phytother Res PTR 28(4):517–525

    Article  CAS  PubMed  Google Scholar 

  38. Du Z, Sha X (2017) Demethoxycurcumin inhibited human epithelia ovarian cancer cells’ growth via up-regulating miR-551a. TumourBiol J Intern SocOncodevelopBiol Med 39(3):1010428317694302

    Google Scholar 

  39. Lin C et al (2018) viaDemethoxycurcumin suppresses migration and invasion of human cervical cancer hela cells inhibition of NF-κB pathways. Anticancer Res 38(5):2761–2769

    CAS  PubMed  Google Scholar 

  40. Anbarasu K, Jayanthi S (2018) Identification of curcumin derivatives as human LMTK3 inhibitors for breast cancer: a docking, dynamics, and MM/PBSA approach. 3 Biotech 8(5):228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sterling J et al (2011) Advances in the biology of bone metastasis: how the skeleton affects tumor behavior. Bone 48(1):6–15

    Article  CAS  PubMed  Google Scholar 

  42. Fecher L, Amaravadi R, Flaherty K (2008) The MAPK pathway in melanoma. CurrOpinOncol 20(2):183–189

    CAS  Google Scholar 

  43. Wang L et al (2019) Curcumin derivative WZ35 inhibits tumor cell growth via ROS-YAP-JNK signaling pathway in breast cancer. J ExpClin Cancer Res CR 38(1):460

    Article  CAS  Google Scholar 

  44. Yao Y et al (2012) HGFK1 inhibits bone metastasis in breast cancer through the TAK1/p38 MAPK signaling pathway. Cancer Gene Ther 19(9):601–608

    Article  CAS  PubMed  Google Scholar 

  45. Guise T (2000) Molecular mechanisms of osteolytic bone metastases. Cancer 88:2892–2898

    Article  CAS  PubMed  Google Scholar 

  46. Roodman G, Dougall W (2008) RANK ligand as a therapeutic target for bone metastases and multiple myeloma. Cancer Treat Rev 34(1):92–101

    Article  CAS  PubMed  Google Scholar 

  47. Nakashima T et al (2011) Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 17(10):1231–1234

    Article  CAS  PubMed  Google Scholar 

  48. Hayder M et al (2011) A phosphorus-based dendrimer targets inflammation and osteoclastogenesis in experimental arthritis. SciTransl Med 3(81):81ra35

    Google Scholar 

  49. Wuerzberger-Davis S et al (2011) Nuclear export of the NF-κB inhibitor IκBα is required for proper B cell and secondary lymphoid tissue formation. Immunity 34(2):188–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Li C et al (2011) Maslinic acid suppresses osteoclastogenesis and prevents ovariectomy-induced bone loss by regulating RANKL-mediated NF-κB and MAPK signaling pathways. J Bone Mineral Res Off J Am Soc Bone Mineral Res 26(3):644–656

    Article  CAS  Google Scholar 

  51. Huang S et al (2017) Tunicamycin potentiates paclitaxel-induced apoptosis through inhibition of PI3K/AKT and MAPK pathways in breast cancer. CancerChemotherPharmacol 80(4):685–696

    CAS  Google Scholar 

Download references

Acknowledgements

This project is supported by grants from Science and Technology Project of Suzhou Science and Technology Bureau (sys2018091, SS2019070), and Key Project of Jiangsu Science and Technology Development Program of Traditional Chinese Medicine (ZD201910).

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Authors and Affiliations

  1. Suzhou TCM Hospital, Affiliated to Nanjing University of Chinese Medicine, , Nanjing, China

    Xiaofeng Shen, Hua Chen, Binjie Lu, Yuanyuan Qin, Guoqiang Liang, Jiangping Wang, Pengfei Yu, Qihan Ma & Yuwei Li

  2. School of Medicine, Shanghai University, Shanghai, China

    Xiaochen Sun

  3. Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China

    Xiaochen Sun

  4. Institute of Translational Medicine, Shanghai University, Shanghai, China

    Chenxi Zhang & Li Su

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  1. Xiaofeng Shen
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  3. Hua Chen
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Contributions

Conceptualization: XS, XS and QM. Data curation: XS and XS. Formal analysis: XS, HC, GL and JW. Funding acquisition: QM and YL. Investigation: HC and PY. Methodology: BL, CZ and JW. Project administration: BL and YL. Resources: YQ, QM and YL. Software: YQ and CZ. Supervision: QM, YL and LS. Validation: QM and YL. Visualization: GL and PY. Writing—original draft: XS and XS. Writing—review and editing: XS, XS, QM and YL.

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Correspondence to Qihan Ma or Yuwei Li.

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Xiaofeng Shen and Xiaochen Sun are co-first authors.

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Shen, X., Sun, X., Chen, H. et al. Demethoxycucumin protects MDA-MB-231 cells induced bone destruction through JNK and ERK pathways inhibition. Cancer Chemother Pharmacol 87, 487–499 (2021). https://doi.org/10.1007/s00280-020-04198-7

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  • DOI: https://doi.org/10.1007/s00280-020-04198-7

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