INSERM 895, Team 2: Cell Death Differentiation and Cancer, Laboratoire d'Oncohématologie, Centre Hospitalier Universitaire de Nice, Nice, France.
Cancer Res. 2010 Feb 1;70(3):1042-52. doi: 10.1158/0008-5472.CAN-09-3537. Epub 2010 Jan 26.
Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy.
饥饿或细胞应激诱导的自噬可以通过维持能量稳态和清除受损的细胞器和蛋白质来使癌细胞存活。有报道称，在应激下，癌细胞会积累蛋白 p62/SQSTM1（p62），但其在自噬调控中的作用存在争议。在这里，我们报告称，植物抗毒素白藜芦醇（RSV）通过 JNK 依赖性 p62 积累触发伊马替尼敏感和耐药性慢性髓系白血病（CML）细胞的自噬。JNK 抑制或 p62 敲低可阻止 RSV 介导的自噬和抗白血病作用。RSV 还刺激 AMPK，从而抑制 mTOR 通路。AMPK 敲低或 mTOR 过表达会损害 RSV 诱导的自噬，但不会激活 JNK。最后，RSV 诱导了来自 CML 患者的 CD34+祖细胞中的 p62 表达和自噬，破坏自噬可保护 CD34+CML 细胞免受 RSV 介导的细胞死亡。我们得出结论，RSV 通过 JNK 介导的 p62 过表达和 AMPK 激活在 CML 细胞中触发自噬性细胞死亡。我们的研究结果表明，JNK 和 AMPK 通路可以通过自噬协同消除 CML 细胞。
