Abstract
We have shown previously that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, but resistance can be reversed through activation of caspase-4 by inhibition of the MEK/ERK pathway. We report in this study that apoptosis was induced by the ER stress inducer thapsigargin or tunicamycin via a caspase-8-mediated pathway in the melanoma cell line Me1007, although the MEK/ERK pathway was activated in this cell line. The high sensitivity of Me1007 to ER stress-induced apoptosis was associated with low expression levels of the apoptosis repressor with caspase recruitment domain (ARC) protein that was expressed at relatively high levels in the resistant melanoma cell lines. Transfection of cDNA encoding ARC into Me1007 cells inhibited both caspase-8 activation and apoptosis induced by thapsigargin or tunicamycin. In contrast, inhibition of ARC by small interfering RNA knockdown sensitized the resistant melanoma cell lines to ER stress-induced apoptosis, which was inhibitable by blockage of caspase-8 activation. Both exogenous and endogenous ARC seemed to predominantly locate to the cytoplasm and mitochondria and could be coimmunoprecipitated with caspase-8. Taken together, ER stress can potentially activate multiple apoptosis signaling pathways in melanoma cells in a context-dependent manner. Whereas the MEK/ERK signaling pathway plays an important role in inhibiting ER stress-induced caspase-4 activation, ARC seems to be critical in blocking activation of caspase-8 in melanoma cells subjected to ER stress.
Highlights
A number of cellular stress conditions, such as nutrient deprivation, hypoxia, alterations in glycosylation status, and disturbances of calcium flux, lead to accumulation and aggregation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) lumen and cause so-called ER stress [1,2,3]
Our previous studies have shown that, in contrast to most melanoma cell lines that are resistant to ER stress–induced apoptosis, Me1007 is highly sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin [12]
It was of much interest that the melanoma cell line Me1007 was highly sensitive to apoptosis induced by the ER stress inducer thapsigargin or tunicamycin
Summary
A number of cellular stress conditions, such as nutrient deprivation, hypoxia, alterations in glycosylation status, and disturbances of calcium flux, lead to accumulation and aggregation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) lumen and cause so-called ER stress [1,2,3]. We have shown that ER stress induces apoptosis in human melanoma cell lines by activation of caspase-4 when the MEK/ERK signaling pathway is inhibited [12]. The majority of melanoma cell lines are otherwise relatively resistant to ER stress–induced apoptosis, except that one line, Me1007, seems to be exceptionally sensitive to apoptosis induced by ER stress inducers the MEK/ ERK pathway is constitutively activated in the cells [12]. This suggests that, besides activation of caspase-4, ER stress can potentially initiate other apoptotic mechanism(s), which is less sensitive to the inhibitory effect of the MEK/ERK pathway, but blocked in most melanoma cell lines
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