Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. OS Inhibits Migration of Tumor Cells
2.2. Osteocytes Support Breast Cancer Cell Growth under High OS Levels
2.3. Cx43 Hemichannels in Osteocytes Protect Cancer Cell Growth under High OS
2.4. The Inhibitory Effect of Cx43 Hemichannels on Breast Cancer Growth in Bone Is Mitigated in Ovariectomized Mice
2.5. Antioxidant Treatment Increases Tumor Growth in Bone of Δ130-136 Mice
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Measurement of Intracellular ROS
4.3. Wound-Healing Assay
4.4. Cancer Cell Growth under Co-Culturing with Osteocytes
4.5. Animal Models
4.6. Ovariectomy (OVX) Procedure
4.7. Antioxidant Treatment for Mice
4.8. Tumor Cell Intratibial Injection, Bioluminescence, and X-ray Imaging
4.9. Preparation of Bone Tissue Sections and Immunohistochemistry
4.10. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Hernandez, R.K.; Wade, S.W.; Reich, A.; Pirolli, M.; Liede, A.; Lyman, G.H. Incidence of bone metastases in patients with solid tumors: Analysis of oncology electronic medical records in the United States. BMC Cancer 2018, 18, 44. [Google Scholar] [CrossRef] [Green Version]
- Tahara, R.K.; Brewer, T.M.; Theriault, R.L.; Ueno, N.T. Bone Metastasis of Breast Cancer. Adv. Exp. Med. Biol. 2019, 1152, 105–129. [Google Scholar]
- Yang, M.; Liu, C.; Yu, X. Skeletal-related adverse events during bone metastasis of breast cancer: Current status. Discov. Med. 2019, 27, 211–220. [Google Scholar] [PubMed]
- Fornetti, J.; Welm, A.L.; Stewart, S.A. Understanding the Bone in Cancer Metastasis. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2018, 33, 2099–2113. [Google Scholar] [CrossRef] [Green Version]
- Hiraga, T. Bone metastasis: Interaction between cancer cells and bone microenvironment. J. Oral Biosci. 2019, 61, 95–98. [Google Scholar] [CrossRef] [PubMed]
- Place, A.E.; Huh, S.J.; Polyak, K. The microenvironment in breast cancer progression: Biology and implications for treatment. Breast Cancer Res. BCR 2011, 13, 227. [Google Scholar] [CrossRef] [Green Version]
- Bonewald, L.F. Osteocytes as dynamic multifunctional cells. Ann. N. Y. Acad. Sci. 2007, 1116, 281–290. [Google Scholar] [CrossRef]
- Matsuo, K. Cross-talk among bone cells. Curr. Opin. Nephrol. Hypertens. 2009, 18, 292–297. [Google Scholar] [CrossRef] [PubMed]
- Florencio-Silva, R.; Sasso, G.R.; Sasso-Cerri, E.; Simoes, M.J.; Cerri, P.S. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells. BioMed. Res. Int. 2015, 2015, 421746. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Goodenough, D.A.; Paul, D.L. Beyond the gap: Functions of unpaired connexon channels, Nature reviews. Mol. Cell Biol. 2003, 4, 285–294. [Google Scholar]
- Stains, J.P.; Civitelli, R. Gap junctions in skeletal development and function. Biochim. Biophys. Acta 2005, 1719, 69–81. [Google Scholar] [CrossRef] [Green Version]
- Batra, N.; Kar, R.; Jiang, J.X. Gap junctions and hemichannels in signal transmission, function and development of bone. Biochim. Biophys. Acta (BBA)-Biomembr. 2012, 1818, 1909–1918. [Google Scholar] [CrossRef] [Green Version]
- Xu, H.; Gu, S.; Riquelme, M.A.; Burra, S.; Callaway, D.; Cheng, H.; Guda, T.; Schmitz, J.; Fajardo, R.J.; Werner, S.L.; et al. Connexin 43 channels are essential for normal bone structure and osteocyte viability. J. Bone Miner. Res. 2015, 30, 436–448. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ma, L.; Hua, R.; Tian, Y.; Cheng, H.; Fajardo, R.J.; Pearson, J.J.; Guda, T.; Shropshire, D.B.; Gu, S.; Jiang, J.X. Connexin 43 hemichannels protect bone loss during estrogen deficiency. Bone Res. 2019, 7, 11. [Google Scholar] [CrossRef] [PubMed]
- Kar, R.; Riquelme, M.A.; Werner, S.; Jiang, J.X. Connexin 43 channels protect osteocytes against oxidative stress-induced cell death. J. Bone Miner. Res. 2013, 28, 1611–1621. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, J.Z.; Riquelme, M.A.; Gao, X.; Ellies, L.G.; Sun, L.Z.; Jiang, J.X. Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis. Oncogene 2015, 34, 1831–1842. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, J.Z.; Riquelme, M.A.; Gu, S.; Kar, R.; Gao, X.; Sun, L.; Jiang, J.X. Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis. Oncogene 2016, 35, 5597–5607. [Google Scholar] [CrossRef] [Green Version]
- Waris, G.; Ahsan, H. Reactive oxygen species: Role in the development of cancer and various chronic conditions. J. Carcinog. 2006, 5, 14. [Google Scholar] [CrossRef]
- Siller-Jackson, A.J.; Burra, S.; Gu, S.; Xia, X.; Bonewald, L.F.; Sprague, E.; Jiang, J.X. Adaptation of connexin 43-hemichannel prostaglandin release to mechanical loading. J. Biol. Chem. 2008, 283, 26374–26382. [Google Scholar] [CrossRef] [Green Version]
- Hayes, J.D.; Dinkova-Kostova, A.T.; Tew, K.D. Oxidative Stress in Cancer. Cancer Cell 2020, 38, 167–197. [Google Scholar] [CrossRef]
- Gill, J.G.; Piskounova, E.; Morrison, S.J. Cancer, Oxidative Stress, and Metastasis. Cold Spring Harb. Symp. Quant. Biol. 2016, 81, 163–175. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Harris, I.S.; Treloar, A.E.; Inoue, S.; Sasaki, M.; Gorrini, C.; Lee, K.C.; Yung, K.Y.; Brenner, D.; Knobbe-Thomsen, C.B.; Cox, M.A.; et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 2015, 27, 211–222. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Piskounova, E.; Agathocleous, M.; Murphy, M.M.; Hu, Z.; Huddlestun, S.E.; Zhao, Z.; Leitch, A.M.; Johnson, T.M.; DeBerardinis, R.J.; Morrison, S.J. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 2015, 527, 186–191. [Google Scholar] [CrossRef] [Green Version]
- Loiselle, A.E.; Jiang, J.X.; Donahue, H.J. Gap junction and hemichannel functions in osteocytes. Bone 2013, 54, 205–212. [Google Scholar] [CrossRef] [PubMed]
- Pogoda, K.; Kameritsch, P.; Retamal, M.A.; Vega, J.L. Regulation of gap junction channels and hemichannels by phosphorylation and redox changes: A revision. BMC Cell Biol. 2016, 17 (Suppl. 1), 11. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Retamal, M.A.; Reyes, E.P.; Garcia, I.E.; Pinto, B.; Martinez, A.D.; Gonzalez, C. Diseases associated with leaky hemichannels. Front. Cell. Neurosci. 2015, 9, 267. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saez, J.C.; Schalper, K.A.; Retamal, M.A.; Orellana, J.A.; Shoji, K.F.; Bennett, M.V. Cell membrane permeabilization via connexin hemichannels in living and dying cells. Exp. Cell Res. 2010, 316, 2377–2389. [Google Scholar] [CrossRef] [PubMed]
- Ramkumar, V.; Hallam, D.M.; Nie, Z. Adenosine, oxidative stress and cytoprotection. Jpn. J. Pharmacol. 2001, 86, 265–274. [Google Scholar] [CrossRef] [Green Version]
- Sharma, D.; Larriera, A.I.; Palacio-Mancheno, P.E.; Gatti, V.; Fritton, J.C.; Bromage, T.G.; Cardoso, L.; Doty, S.B.; Fritton, S.P. The effects of estrogen deficiency on cortical bone microporosity and mineralization. Bone 2018, 110, 1–10. [Google Scholar] [CrossRef]
- Komori, T. Animal models for osteoporosis. Eur. J. Pharmacol. 2015, 759, 287–294. [Google Scholar] [CrossRef]
- Weitzmann, M.N.; Pacifici, R. Estrogen deficiency and bone loss: An inflammatory tale. J. Clin. Investig. 2006, 116, 1186–1194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lean, J.M.; Davies, J.T.; Fuller, K.; Jagger, C.J.; Kirstein, B.; Partington, G.A.; Urry, Z.L.; Chambers, T.J. A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J. Clin. Investig. 2003, 112, 915–923. [Google Scholar] [CrossRef] [Green Version]
- Salamanna, F.; Borsari, V.; Contartese, D.; Aldini, N.N.; Fini, M. Link between estrogen deficiency osteoporosis and susceptibility to bone metastases: A way towards precision medicine in cancer patients. Breast 2018, 41, 42–50. [Google Scholar] [CrossRef]
- Ibe, I.K.; Sahlstrom, A.; White, A.; Henderson, S.E.; Lee, F.Y. Metastatic Cancers to Bone: An Overview and Cancer-Induced Bone Loss. Instr. Course Lect. 2019, 68, 547–556. [Google Scholar]
- Aldini, G.; Altomare, A.; Baron, G.; Vistoli, G.; Carini, M.; Borsani, L.; Sergio, F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why. Free Radic. Res. 2018, 52, 751–762. [Google Scholar] [CrossRef] [PubMed]
- Kelly, G.S. Clinical applications of N-acetylcysteine. Altern. Med. Rev. J. Clin. Ther. 1998, 3, 114–127. [Google Scholar]
- van Zandwijk, N. N-acetylcysteine (NAC) and glutathione (GSH): Antioxidant and chemopreventive properties, with special reference to lung cancer. J. Cell. Biochem. 1995, 22, 24–32. [Google Scholar] [CrossRef]
- Chen, J.X.; Liu, A.; Lee, M.J.; Wang, H.; Yu, S.; Chi, E.; Reuhl, K.; Suh, N.; Yang, C.S. delta- and gamma-tocopherols inhibit phIP/DSS-induced colon carcinogenesis by protection against early cellular and DNA damages. Mol. Carcinog. 2017, 56, 172–183. [Google Scholar] [CrossRef] [Green Version]
- Somanah, J.; Ramsaha, S.; Verma, S.; Kumar, A.; Sharma, P.; Singh, R.K.; Aruoma, O.I.; Bourdon, E.; Bahorun, T. Fermented papaya preparation modulates the progression of N-methyl-N-nitrosourea induced hepatocellular carcinoma in Balb/c mice. Life Sci. 2016, 151, 330–338. [Google Scholar] [CrossRef] [PubMed]
- Kasala, E.R.; Bodduluru, L.N.; Barua, C.C.; Madhana, R.M.; Dahiya, V.; Budhani, M.K.; Mallugari, R.R.; Maramreddy, S.R.; Gogoi, R. Chemopreventive effect of chrysin, a dietary flavone against benzo(a)pyrene induced lung carcinogenesis in Swiss albino mice. Pharmacol. Rep. PR 2016, 68, 310–318. [Google Scholar] [CrossRef]
- Gueritat, J.; Lefeuvre-Orfila, L.; Vincent, S.; Cretual, A.; Ravanat, J.L.; Gratas-Delamarche, A.; Rannou-Bekono, F.; Rebillard, A. Exercise training combined with antioxidant supplementation prevents the antiproliferative activity of their single treatment in prostate cancer through inhibition of redox adaptation. Free Radic. Biol. Med. 2014, 77, 95–105. [Google Scholar] [CrossRef]
- Assi, M.; Derbre, F.; Lefeuvre-Orfila, L.; Rebillard, A. Antioxidant supplementation accelerates cachexia development by promoting tumor growth in C26 tumor-bearing mice. Free Radic. Biol. Med. 2016, 91, 204–214. [Google Scholar] [CrossRef] [PubMed]
- le Gal, K.; Ibrahim, M.X.; Wiel, C.; Sayin, V.I.; Akula, M.K.; Karlsson, C.; Dalin, M.G.; Akyurek, L.M.; Lindahl, P.; Nilsson, J.; et al. Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med. 2015, 7, 308re8. [Google Scholar] [CrossRef] [PubMed]
- Portakal, O.; Ozkaya, O.; Inal, M.E.; Bozan, B.; Kosan, M.; Sayek, I. Coenzyme Q10 concentrations and antioxidant status in tissues of breast cancer patients. Clin. Biochem. 2000, 33, 279–284. [Google Scholar] [CrossRef]
- Sayin, V.I.; Ibrahim, M.X.; Larsson, E.; Nilsson, J.A.; Lindahl, P.; Bergo, M.O. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med. 2014, 6, 221ra15. [Google Scholar] [CrossRef] [PubMed]
- Sun, X.; Wang, W.; Chen, J.; Cai, X.; Yang, J.; Yang, Y.; Yan, H.; Cheng, X.; Ye, J.; Lu, W.; et al. The Natural Diterpenoid Isoforretin A Inhibits Thioredoxin-1 and Triggers Potent ROS-Mediated Antitumor Effects. Cancer Res. 2017, 77, 926–936. [Google Scholar] [CrossRef] [Green Version]
- Zelko, I.N.; Mariani, T.J.; Folz, R.J. Superoxide dismutase multigene family: A comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic. Biol. Med. 2002, 33, 337–349. [Google Scholar] [CrossRef]
- Fang, X.; Huang, T.; Zhu, Y.; Yan, Q.; Chi, Y.; Jiang, J.X.; Wang, P.; Matsue, H.; Kitamura, M.; Yao, Y. Connexin43 hemichannels contribute to cadmium-induced oxidative stress and cell injury. Antioxid. Redox Signal. 2011, 14, 2427–2439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Orellana, J.A.; Shoji, K.F.; Abudara, V.; Ezan, P.; Amigou, E.; Sáez, P.J.; Jiang, J.X.; Naus, C.C.; Sáez, J.C.; Giaume, C. Amyloid β-induced death in neurons involves glial and neuronal hemichannels. J. Neurosci. 2011, 31, 4962–4977. [Google Scholar] [CrossRef]
- Lai, C.F.; Cheng, S.L.; Mbalaviele, G.; Donsante, C.; Watkins, M.; Radice, G.L.; Civitelli, R. Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice. J. Bone Miner. Res. 2006, 21, 1897–1906. [Google Scholar] [CrossRef] [PubMed]
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Tian, Y.; Riquelme, M.A.; Tu, C.; Quan, Y.; Liu, X.; Sun, L.-Z.; Jiang, J.X. Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth. Cancers 2021, 13, 6343. https://doi.org/10.3390/cancers13246343
Tian Y, Riquelme MA, Tu C, Quan Y, Liu X, Sun L-Z, Jiang JX. Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth. Cancers. 2021; 13(24):6343. https://doi.org/10.3390/cancers13246343
Chicago/Turabian StyleTian, Yi, Manuel A. Riquelme, Chao Tu, Yumeng Quan, Xiaowen Liu, Lu-Zhe Sun, and Jean X. Jiang. 2021. "Osteocytic Connexin Hemichannels Modulate Oxidative Bone Microenvironment and Breast Cancer Growth" Cancers 13, no. 24: 6343. https://doi.org/10.3390/cancers13246343