Endoplasmic reticulum (ER) stress triggers apoptosis by activating Bim in diverse types of cells, which involves dephosphorylation of BimEL by protein phosphatase 2A (PP2A).,However, melanoma cells are largely resistant to ER stress-induced apoptosis, suggesting that Bim activation is suppressed in melanoma cells undergoing ER stress.,We show here that ER stress reduces PP2A activity leading to increased ERK activation and subsequent phosphorylation and proteasomal degradation of BimEL.,Despite sustained upregulation of Bim at the transcriptional level, the BimEL protein expression was downregulated after an initial increase in melanoma cells subjected to pharmacological ER stress.,This was mediated by increased activity of ERK, whereas the phosphatase activity of PP2A was reduced by ER stress in melanoma cells.,The increase in ERK activation was, at least in part, due to reduced dephosphorylation by PP2A, which was associated with downregulation of the PP2A catalytic C subunit.,Notably, instead of direct dephosphorylation of BimEL, PP2A inhibited its phosphorylation indirectly through dephosphorylation of ERK in melanoma cells.,Taken together, these results identify downregualtion of PP2A activity as an important protective mechanism of melanoma cells against ER stress-induced apoptosis.
The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas.,Very recently, selective and potent BRAF inhibitors have been developed.,Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents.,Among these, NFκB is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis.,Inhibition of NF-κB activation appears to be a very promising option for anti-cancer therapies.