Epidermal Growth Factor Receptor Signaling and Crosstalk With Aspartate-β-Hydroxylase Modulate Chondrosarcoma Cell...

Aspartate β-Hydroxylase (ASPH) is an oncofetal protein overexpressed in malignancies, including chondrosarcoma. Although its functional roles in malignant neoplastic cell motility and invasiveness have been linked to hydroxylation of epidermal growth factor (EGF)-like domains expressed in molecules such as Notch and Jagged, its relationship to EGF receptor (EGFR) signaling has not been investigated. This study utilized CS-1 (high grade) and CDS-11 (intermediate grade) human chondrosarcoma cell lines to characterize the effects of EGFR stimulation on ASPH expression and function.

CS-1 and CDS11 cells were treated with the trophic factors EGF, TGF-α, TGF-β, IGF-1, or vehicle (0.5% FBS) and assayed for growth, viability, morphology, motility, invasiveness, EGFR activation, Notch pathway gene expression, and ASPH expression.

EGF, TGF-α, and TGF-β increased the expression of EGFR, proliferating cell nuclear antigen (PCNA), and ASPH-FB50, EGF and TGF-β stimulated tyrosine-phosphorylated (pY) EGFR, and EGF and TGF-α stimulated vimentin in the CDS11 but not CS-1 cells. The stimulatory effects of EGF, TGF-α, and TGF-β were associated with significantly increased directional motility and invasion. Further studies suggested that the effects of EGFR pathway stimulation by TGF-β may be mediated by differential increases in the expression of IGF1R, IRS1, JAGGED, and HES or HEY NOTCH transcription factors.

The results of these investigations suggest important roles for EGF, TGF-α, and TGF-β regulation of growth, motility, invasiveness, and ASPH-FB50 immunoreactivity via EGFR in CDS11 chondrosarcoma cells. In addition, CDS11 cellular responses to TGF-β may have been mediated by increased ASPH protein expression together with IGF/IRS and Notch network crosstalk. Additional therapeutic strategies for chondrosarcoma may include EGFR and ASPH inhibitors in combination with conventional chemotherapy.