Targeting leucine addiction and autophagy in melanoma.
Targeting leucine addiction and autophagy in melanoma.
复制标题
针对黑色素瘤中的亮氨酸成瘾和自噬。
DOI：
10.1111/j.1755-148x.2011.00877.x
复制
发表时间：
2011
影响因子：
4.3
通讯作者：
Diaz-Meco,MariaT
中科院分区：
文献类型：
--
作者：
Diaz-Meco,MariaT
Melanoma is an increasingly prevalent cancer that is known for being aggressive. At advanced stages, the prognosis is poor and patient survival rates are low. Melanoma quickly progresses to metastasis and becomes highly resistant to current therapies. Somatic mutations in B-RAF and RAS, with BRAFV600E being the most common one, have been found with high incidence in malignant melanoma, which results in constitutive activation of the MAPK signaling pathway. Consequently, unraveling the molecular mechanisms controlled by hyperactivation of the RAS/RAF/MAPK pathway is critical to gaining a better understanding of how melanoma tumors grow and progress and to identify new therapeutic strategies. Initial efforts in this direction have suggested that the targeted inhibition of components of this cascade is a promising approach. That is, RAF inhibitors display remarkable clinical activity in melanoma tumors with BRAFV600E mutations. However, resistance to these drugs invariably arises resulting in reduced clinical responses. Interestingly, there is mounting evidence that these oncogenic mutations could influence nutrient-sensing and metabolic pathways that modulate the survival of cancer cells (Mathew and White, 2011). In this regard, autophagy has emerged as a central player in this process and, therefore, as a potential cancer target. Autophagy is a lysosome-dependent mechanism for the degradation of cytoplasmic proteins, damaged organelles and aggregates that can be induced by nutrient deprivation (Mathew and White, 2011). There are data suggesting an important role for autophagy as a common mechanism underlying resistance to metabolic stress and cancer therapy.A recent study from the Sabatini laboratory suggests a novel intervention to promote melanoma cell death by taking advantage of a metabolic disadvantage of these cells in terms of the activation of autophagy during nutrient stress. The authors focused on the response of melanoma cells, with regard to survival versus death, when starved of different essential amino acids. Sabatini and co-workers found that melanoma cells with hyperactivated RAS–MEK signaling were sensitive to leucine deprivation, which induced a mitochondrial apoptotic cascade triggered by a failure to activate autophagy (Fig. 1). This effect was selective for melanoma cells and did not occur in normal cells, which offers an interesting therapeutic opportunity. These authors went on to show, in in vivo melanoma xenografts, that dietary leucine deprivation combined with chloroquine, an autophagy inhibitor, had a synergistic effect on tumor size reduction concomitant with the induction of melanoma cell death. A critical question, from a mechanistic point of view, is how oncogenic activation of the RAS–MEK cascade regulates the melanoma cell’s dependence on leucine for survival. The authors propose that this effect is mediated through mTOR complex 1 (mTORC1), an amino acid sensor and a master-negative regulator of autophagy (Fig. 1). It is now very well established that nutrient starvation inhibits the activation of autophagy by mTORC1. However, in melanoma cells with activated RAS–MEK signaling, leucine deprivation is not sufficient to inhibit mTORC1 and therefore does not trigger the autophagic survival mechanism. This is a very important observation that should be considered in the context of another recent report demonstrating a MAPK-dependent mechanism for the regulation of autophagy independent of mTOR, through the control of the transcription factor EB (TFEB), a master gene for lysosomal biogenesis and autophagy (Settembre et al., 2011). According to these data, MAPK …
