Abstract
Cutaneous melanoma is often resistant to chemo- and radiotherapy. This resistance has recently been demonstrated to be due, at least in part, to high activating transcription factor 2 (ATF-2) activity in these tumors. In concordance with these reports, we found that B16 mouse melanoma cells had higher levels of ATF-2 than immortalized, but non-malignant mouse melanocytes. In addition, the melanoma cells had a much higher amount of phosphorylated (active) ATF-2 than the immortalized melanocytes. In the course of determining how retinoic acid (RA) stimulates activating protein-1 (AP-1) activity in B16 melanoma, we discovered that this retinoid decreased the phosphorylation of ATF-2. It appears that this effect is mediated through p38 MAPK, because RA decreased p38 phosphorylation, and a selective inhibitor of p38 MAPK (SB203580) also inhibited the phosphorylation of ATF-2. Since ATF-2 activity appears to be involved in resistance of melanoma to chemotherapy, we tested the hypothesis that treatment of the melanoma cells with RA would sensitize them to the growth-inhibitory effect of taxol. We found that pretreatment of B16 cells with RA decreased the IC50 from 50 nM to 1 nM taxol. On the basis of these findings and our previous work on AP-1, we propose a model in which treatment of B16 cells with RA decreases the phosphorylation of ATF-2, which results in less dimer formation with Jun. The "freed-up" Jun can then form a heterodimer with Fos, resulting in the increased AP-1 activity observed in RA-treated B16 cells. Shifting the balance from predominantly ATF-2:Jun dimers to a higher amount of Jun:Fos dimers could lead a change in target gene expression that reduces resistance to chemotherapeutic drugs and contributes to the pathway by which RA arrests proliferation and induces differentiation.
Highlights
The incidence of cutaneous melanoma has been rapidly increasing in the past few years
Expression and phosphorylation of activating transcription factor 2 (ATF-2) protein in malignant mouse melanoma cells versus non-malignant mouse melanocytes Previous work from our laboratory has shown that retinoic acid (RA) induces activating protein-1 (AP-1) transcriptional activity in B16 mouse melanoma cells [12,13]
We have previously found that treatment of B16 mouse melanoma cells with alltrans-RA induces a two to four-fold increase in AP-1 transcriptional activity, and this increase appears to be required for growth arrest and differentiation [13]
Summary
The incidence of cutaneous melanoma has been rapidly increasing in the past few years. Treatment of patients with metastatic melanoma has been problematic because of its poor response to chemo- and radiotherapy. It has been found that activating transcription factor 2 (ATF-2) is responsible, at least in part, for resistance of melanoma to chemo- and radiotherapy [1]. Jun and Fos bZIP families, together with ATF-2, constitute the activating protein-1 (AP-1) transcription factor family. ATF-2 is transcriptionally inactive because of its intramolecular inhibition, in which the ATF-2 activation domain and bZIP domain bind to each other [5]. ATF2 is known to acquire its transcriptional activity upon phosphorylation by MAP kinases, including JNK and p38 [5,6]. Phosphorylation at two threonine sites within the N-terminal activation domain leads to ATF-2 conformational changes, which releases the intramolecular inhibition
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