Astrocyte elevated gene‑1 regulates osteosarcoma cell invasion and chemoresistance via endothelin‑1/endothelin A receptor signaling
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Affiliations: Department of Orthopaedics, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
- Published online on: December 3, 2012 https://doi.org/10.3892/ol.2012.1056
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505-510
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Abstract
Astrocyte elevated gene‑1 (AEG‑1) and endothelin‑1 (ET‑1)/endothelin A receptor (ETAR) signaling have been demonstrated to be important in osteosarcoma (OS) progression. In the present study, we explored the interaction between AEG‑1 and ET‑1/ETAR signaling in OS cells, and investigated the mechanism(s) through which the functional interaction may impact OS cell invasion and chemoresistance. Overexpression and knockdown of AEG‑1 were performed in Saos‑2 and MG‑63 OS cells, respectively. Overexpression of AEG‑1 in Saos‑2 cells significantly increased ET‑1 expression (at both the mRNA and protein levels), cell invasion, MMP‑2 expression and cell survival against cisplatin. These effects were eradicated using a selective phosphatidylinositol 3‑kinase (PI3K) inhibitor, LY294002, or a selective ETAR inhibitor, BQ123. Knockdown of AEG‑1 in MG‑63 cells significantly decreased ET‑1 expression (at both the mRNA and protein levels), cell invasion, MMP‑2 expression and cell survival against cisplatin. Exogenous ET‑1 restored cell invasion and MMP‑2 expression levels in MG‑63 cells, in which AEG‑1 had been knocked down, in the presence of LY294002, but not in the presence of BQ123. However, exogenous ET‑1 only partially rescued cell survival against cisplatin-induced apoptosis in the presence of LY294002, in cells in which AEG‑1 had been knocked down. In conclusion, we have demonstrated that AEG‑1 regulates ET‑1 expression at the transcriptional level in a PI3K-dependent manner in OS cells. Downstream of PI3K, ET‑1/ETAR signaling primarily mediates the promoting effect of AEG‑1 on OS cell invasion, likely through the upregulation of MMP‑2 expression, thus, ET‑1/ETAR signaling partially, but significantly, mediates the AEG‑1‑induced chemoresistance in OS cells. To the best of our knowledge, this study has provided the first evidence of a functional association between AEG‑1 and ET‑1/ETAR signaling in OS cells, which adds novel insights into the molecular mechanism of OS metastasis and chemoresistance.
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