Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors.
Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors.
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DOI：
10.1038/s41419-018-0340-4
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发表时间：
2018-02-27
影响因子：
9
通讯作者：
Kluza J
中科院分区：
文献类型：
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作者：
Khamari R;Trinh A;Gabert PE;Corazao-Rozas P;Riveros-Cruz S;Balayssac S;Malet-Martino M;Dekiouk S;Joncquel Chevalier Curt M;Maboudou P;Garçon G;Ravasi L;Guerreschi P;Mortier L;Quesnel B;Marchetti P;Kluza J
BRAF和MEK抑制剂联合靶向治疗已被批准为BRAF突变黑色素瘤的一线治疗方法。然而，大多数患者在治疗后几个月内就会出现疾病进展。代谢适应已经在对BRAF抑制剂(BRAFi)的获得性抵抗的背景下被描述。BRAFi耐药黑色素瘤的特点是线粒体氧化磷酸化增加，更容易被线粒体靶向药物诱导细胞死亡。耐BRAFi的黑色素瘤还表现出氧化应激增强，这是由于线粒体耗氧增加所致。为了了解在氧化应激背景下耐BRAFi黑色素瘤细胞存活的机制，我们建立了一个临床前小鼠模型，该模型准确地概括了在体内获得对MAPK抑制剂的耐药性，包括几种BRAF或MEK抑制剂单独和联合使用。利用小鼠模型和小鼠肿瘤产生的黑色素瘤细胞系，我们证实了抗性的获得与线粒体氧化磷酸化的增加以及谷氨酰胺代谢的重要性有关。此外，我们已经证明，耐BRAFi黑色素瘤可以调整线粒体代谢，以支持葡萄糖衍生的谷氨酸合成，从而增加谷胱甘肽的含量。此外，耐BRAFi黑色素瘤表现出NRF-2途径的强烈激活，导致参与还原型谷胱甘肽再生的戊糖磷酸途径增加，并增加XCT的表达，XCT是细胞内谷胱甘肽合成所需的摄取胱氨酸所必需的XC-氨基酸转运体的组成部分。所有这些代谢修饰都维持谷胱甘肽水平，并有助于细胞内氧化还原平衡，以允许耐BRAFi黑色素瘤细胞存活。
Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc—amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.
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影响因子：
7.7
作者：
Sayin, Volkan I.;LeBoeuf, Sarah E.;Papagiannakopoulos, Thales
通讯作者：
Papagiannakopoulos, Thales
影响因子：
28.2
作者：
Parmenter TJ;Kleinschmidt M;Kinross KM;Bond ST;Li J;Kaadige MR;Rao A;Sheppard KE;Hugo W;Pupo GM;Pearson RB;McGee SL;Long GV;Scolyer RA;Rizos H;Lo RS;Cullinane C;Ayer DE;Ribas A;Johnstone RW;Hicks RJ;McArthur GA
通讯作者：
McArthur GA
影响因子：
6.6
作者：
Jung, Kyeong-Ah;Lee, Sujin;Kwak, Mi-Kyoung
通讯作者：
Kwak, Mi-Kyoung
影响因子：
45.3
作者：
Long, Georgina V.;Weber, Jeffrey S.;Flaherty, Keith T.
通讯作者：
Flaherty, Keith T.
通过抑制B-RAFV600E诱导的人类黑色素瘤细胞的凋亡涉及BIMS的优先剪接。
影响因子：
9
作者：
通讯作者：
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