Effect of mesenchymal stem cells on hypoxia‑induced desensitization of β2-adrenergic receptors in rat osteosarcoma cells

Kido,Akira; Yoshitani,Kazuhiro; Shimizu,Takamasa; Akahane,Manabu; Fujii,Hiromasa; Tsukamoto,Shinji; Kondo,Yumiko; Honoki,Kanya; Imano,Motohiro; Tanaka,Yasuhito

doi:10.3892/ol.2012.813

Effect of mesenchymal stem cells on hypoxia‑induced desensitization of β2-adrenergic receptors in rat osteosarcoma cells

Authors:
- Akira Kido
- Kazuhiro Yoshitani
- Takamasa Shimizu
- Manabu Akahane
- Hiromasa Fujii
- Shinji Tsukamoto
- Yumiko Kondo
- Kanya Honoki
- Motohiro Imano
- Yasuhito Tanaka
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Affiliations: Department of Orthopedic Surgery, School of Medicine, Nara Medical University, Nara, Japan, Department of Public Health, Health Management and Policy, School of Medicine, Nara Medical University, Nara, Japan, Department of Surgery, Kinki University Faculty of Medicine, Osaka, Japan
Published online on: July 19, 2012 https://doi.org/10.3892/ol.2012.813
Pages: 745-750

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Abstract

The β2-adrenergic receptor (β2AR) mediates the effects of chronic stress in several neoplasms, however, β2AR signaling is impaired by hypoxia in various tissues. While hypoxia is a common feature significant in the progression of solid tumors, little is known about the effect of hypoxia on β2AR signaling in the tumor microenvironment. Previously, it has been reported that the systemic administration of mesenchymal stem cells (MSCs) increased the engraftment and metastatic colonization of rat osteosarcoma (OS) cells. In the current study, the effect of MSCs on the hypoxia-induced desensitization of the β2AR in OS cells was investigated. Epinephrine, norepinephrine and isoproterenol increased the cellular proliferation of the rat OS cell line COS1NR and rat MSCs in a dose‑dependent and β2AR antagonist-sensitive manner. While isoproterenol had significant proliferative effects on MSCs under normoxic and hypoxic conditions, COS1NR cells did not respond under hypoxic conditions. A sensitivity assay for the β2AR revealed that hypoxia impaired the sensitivity of COS1NR cells, whereas hypoxia did not affect MSCs. An immunoassay revealed no significant change in the expression of hypoxia-inducible factor-1α (HIF1α) in COS1NR cells, whilst an immunoassay demonstrated a 15% increase in MSCs following isoproterenol stimulation. In COS1NR cells co-cultured with MSCs under hypoxic conditions, isoproterenol caused a significant increase in proliferation and this effect was inhibited by an anti-interleukin (IL)-6 antibody. A tumor formation assay in syngeneic rats revealed that the systemic administration of MSCs enhances the growth of OS and the effect of MSCs was inhibited by IL-6 neutralization. In conclusion, MSCs are resistant to the hypoxia-induced desensitization to β2AR. Hypoxia caused a siginificant desensitization of the β2AR in COS1NR cells alone, whereas MSCs may support tumor progression through cellular interactions.

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