Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Cancer Cell. 2011 May 17;19(5):613-28. doi: 10.1016/j.ccr.2011.03.012.
Autophagy is of increasing interest as a target for cancer therapy. We find that leucine deprivation causes the caspase-dependent apoptotic death of melanoma cells because it fails to appropriately activate autophagy. Hyperactivation of the RAS-MEK pathway, which is common in melanoma, prevents leucine deprivation from inhibiting mTORC1, the main repressor of autophagy under nutrient-rich conditions. In an in vivo tumor xenograft model, the combination of a leucine-free diet and an autophagy inhibitor synergistically suppresses the growth of human melanoma tumors and triggers widespread apoptosis of the cancer cells. Together, our study represents proof of principle that anticancer effects can be obtained with a combination of autophagy inhibition and strategies to deprive tumors of leucine.
自噬作为癌症治疗的靶点越来越受到关注。我们发现亮氨酸缺乏会导致黑色素瘤细胞发生 caspase 依赖性凋亡，因为它不能适当激活自噬。RAS-MEK 通路的过度激活在黑色素瘤中很常见，它阻止了亮氨酸缺乏对 mTORC1 的抑制，mTORC1 是营养丰富条件下自噬的主要抑制剂。在体内肿瘤异种移植模型中，无亮氨酸饮食和自噬抑制剂的联合使用协同抑制了人黑色素瘤肿瘤的生长，并引发了癌细胞的广泛凋亡。总之，我们的研究证明了通过自噬抑制和剥夺肿瘤亮氨酸的策略相结合可以获得抗癌效果的原理。
