Institute of Biochemistry, Hannover Medical School, Hannover, Germany.
PLoS One. 2011;6(8):e23054. doi: 10.1371/journal.pone.0023054. Epub 2011 Aug 10.
SB202190, a widely used inhibitor of p38 MAPKα and β, was recently described to induce autophagic vacuoles and cell death in colon and ovarian cancer cells lines and, therefore, this effect was supposed to be specific for transformed cells and to open therapeutic options. Here, we demonstrate that SB202190 and the structurally related inhibitor SB203580 induce pro-autophagic gene expression and vacuole formation in various cancer and non-cancer cell lines of human, rat, mouse and hamster origin. This effect seems to induce defective autophagy leading to the accumulation of acidic vacuoles, p62 protein and lipid conjugated LC3. Using further p38 inhibitors we show that p38 MAPK inhibition is not sufficient for the autophagic response. In line with these results, expression of a SB202190-resistant mutant of p38α, which significantly increases activity of the p38 pathway under inhibitory conditions, does not block SB202190-dependent vacuole formation, indicating that lack of p38α activity is not necessary for this effect. Obviously, the induction of autophagic vacuole formation by SB203580 and SB202190 is due to off-target effects of these inhibitors on post-translational protein modifications, such as phosphorylation of the MAPKs ERK1/2 and JNK1/2, ribosomal protein S6, and PKB/Akt. Interestingly, the PI3K-inhibitor wortmannin induces transient vacuole formation indicating that the PI3K-PKB/Akt-mTOR pathway is essential for preventing autophagy and that cross-inhibition of this pathway by SB202190 could be the reason for the early part of the effect observed.
SB202190 是一种广泛应用的 p38 MAPKα 和 β 抑制剂，最近被描述为在结肠和卵巢癌细胞系中诱导自噬空泡和细胞死亡，因此，这种效应被认为是针对转化细胞的特异性，并为治疗提供了新的选择。在这里，我们证明 SB202190 和结构相关的抑制剂 SB203580 诱导多种人类、大鼠、小鼠和仓鼠来源的癌症和非癌细胞系中促自噬基因表达和空泡形成。这种效应似乎诱导了缺陷型自噬，导致酸性空泡、p62 蛋白和脂质结合 LC3 的积累。使用进一步的 p38 抑制剂，我们表明 p38 MAPK 抑制不足以引起自噬反应。与这些结果一致，表达一种 SB202190 抗性突变体的 p38α，在抑制条件下显著增加 p38 通路的活性，不会阻断 SB202190 依赖性空泡形成，表明缺乏 p38α 活性不是这种效应所必需的。显然，SB203580 和 SB202190 诱导自噬空泡形成是由于这些抑制剂对翻译后蛋白修饰的脱靶效应，如 MAPKs ERK1/2 和 JNK1/2、核糖体蛋白 S6 和 PKB/Akt 的磷酸化。有趣的是，PI3K 抑制剂 wortmannin 诱导短暂的空泡形成，表明 PI3K-PKB/Akt-mTOR 途径对于防止自噬是必要的，并且 SB202190 对该途径的交叉抑制可能是观察到的早期效应的原因。
