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• W2899381234 abstract "745 The EGFR is frequently expressed in breast cancer cells and its expression has been associated with poor prognosis, increased risk of recurrence, and poor response to endocrine therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines. However, we have shown previously that the majority of breast cancer cell lines are resistant to TRAIL-mediated apoptosis. We investigated if inhibition of EGFR signaling could enhance TRAIL-induced apoptosis in breast cancer cells. We found that AG 1478, a specific tyrosine kinase inhibitor of the EGFR, enhanced TRAIL-induced apoptosis in both TRAIL-sensitive and TRAIL-resistant breast cancer cell lines which expressed EGFR ( i.e. , MB231 and MB468). In contrast, AG 1478 did not increase the TRAIL sensitivity in the EGFR expressing, non-transformed MCF10A cell line. The combination of AG 1478 and TRAIL resulted in the dramatically enhanced activation of caspases-8/10, -9, and -3 and the cleavage of the caspase substrate, PARP, compared to TRAIL or AG 1478 alone. Apoptosis induced by the combination of AG 1478 and TRAIL and by TRAIL alone was inhibited by the pan-caspase inhibitor ZVAD-FMK. Investigation of downstream signaling pathways in cell lines in which TRAIL-induced apoptosis was enhanced by AG 1478 revealed inhibition of Akt activity. However, direct inhibition of Akt by infecting breast cancer cells with an adenovirus containing dominant negative Akt did not increase TRAIL sensitivity. Also transfecting those same cell lines with constitutively active Akt did not affect TRAIL sensitivity. These results demonstrate that inhibition of Akt is not responsible for the increase in TRAIL-mediated apoptosis induced by EGFR inhibition. Inhibition of PI3-kinase activity with LY-294002 enhanced TRAIL-mediated apoptosis in the breast cancer cell lines similar to that induced by the inhibition of EGFR. Transfection of cells with a constitutively active catalytic subunit of PI3-kinase reduced the effect of EGFR inhibition. Together these data suggest that EGFR inhibition enhances TRAIL-mediated apoptosis by a PI3-kinase dependent but Akt independent mechanism." @default.
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• W2899381234 date "2006-04-15" @default.
• W2899381234 modified "2023-09-23" @default.
• W2899381234 title "Inhibition of epidermal growth factor receptor (EGFR) signaling enhances TRAIL-induced apoptosis in breast cancer cells by a PI3-kinase dependant but Akt independent mechanism" @default.
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