Involvement of ERK in the Regulation of Apoptosis of Breast Cancer Cells

Abstract

The extracellular signal-regulated kinase (ERK) pathway is vital to the regulation of a number of cellular processes, including cell growth, division and apoptosis. As breast cancers frequently demonstrate an increased activation of the ERK kinase pathway, we examined the ability of SU1498, a direct inhibitor of ERK kinase activity, to sensitize cells to apoptosis. Two breast cancer cell lines, MCF-7 and MDA-MB-231, are examined under normal growth and serum starvation conditions. SU1498 inhibited growth and proliferation in treated cells under both conditions, and cell cycle analysis by flow cytometry indicated cell cycle arrest in treated cells. However, increased apoptosis as demonstrated by Annexin-V staining occurred only with a combination of SU1498 and serum starvation. The expression levels of the Bcl-2 protein family members were examined and antiapoptotic Bcl-xL and Bcl-2 were downregulated while proapoptotic Bik was upregulation. This study elucidates the importance of ERK activity in the regulation of apoptosis in breast cancer cells. The ability of SU1498 to sensitize breast cancer cells to apoptosis by inhibition of ERK suggests therapeutic uses. Support by an NSERC Discovery Grant.