The role of GRP78, p-ERK and Bcl-2 proteins in endoplasmic reticulum stress-induced apoptosis and anti-apoptosis in melanoma

Abstract

The generation of anti-apoptotic factors is complex. Previous studies have demonstrated that endoplasmic reticulum (ER) stress results in both apoptosis and anti-apoptosis in some tumours. ER stress may induce apoptosis via multiple pathways. Adaptation of melanoma to ER stress may result in anti-apoptosis and resistance to therapy. The anti-apoptosis mechanisms include RAS/RAF/MEK/ERK activation, increased GRP78 and Mcl-1 protein. In the present study, we sought to better characterise the correlation of the ER stress protein GRP78 expression with ERK activation and Bcl-2 family proteins. The expression of GRP78, Bcl-2 and Mcl-1 in formalin-fixed sections of 135 naevi, primary and metastatic melanoma by immunohistochemistry was examined. p-ERK expression was assessed in 82 of the 135 cases. The correlations of GRP78 with p-ERK, Bcl-2 and Mcl-1 were analysed. The immunoreactive score (IRS) of GRP78 and Mcl-1 were related to melanocytic tumour progression. The intensity of GRP78 and Mcl-1 increased with the progression of melanocytic tumours. In contrast, Bcl-2 showed high expression in melanoma ≤1mm and less expression in melanoma metastases. GRP78 expression increased with increased p-ERK expression (<i>p</i><0.01). GRP78 expression increased with increased expression of Mcl-1 (<i>p</i><0.0001). The findings of this study suggest that activated ERK may enhance GRP78 levels and are consistent with previous results from melanoma cell lines. GRP78 and Mcl-1 expression may play a role in protecting cells from ER stress-induced apoptosis. Bcl-2 is increased in thin melanoma and this suggests that Bcl-2 plays its anti-apoptotic role in the early stage of melanoma progression.