Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma.
Impairment of gamma-glutamyl transferase 1 activity in the metabolic pathogenesis of chromophobe renal cell carcinoma.
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DOI：
10.1073/pnas.1710849115
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发表时间：
2018-07-03
影响因子：
11.1
通讯作者：
Henske EP
中科院分区：
文献类型：
--
作者：
Priolo C;Khabibullin D;Reznik E;Filippakis H;Ogórek B;Kavanagh TR;Nijmeh J;Herbert ZT;Asara JM;Kwiatkowski DJ;Wu CL;Henske EP
肾嫌色细胞癌（ChRCC）的发病机制仍然是一个关键的知识缺口。通过代谢组学，这项研究揭示了ChRCC发病机制的基本代谢机制，对这种罕见的肿瘤类型具有关键的治疗意义，目前尚无特异性靶向治疗方法。进一步了解谷胱甘肽补救途径对线粒体功能、肿瘤进展和靶向治疗的影响，可以深入了解以异常谷胱甘肽补救途径为特征的其他癌症。嫌色性肾细胞癌（ChRCC）占所有散发性肾癌的5%，也可发生在遗传综合征中，包括Birt-Hogg-Dube（BHD）和结节性硬化症（TSC）。ChRCC具有异常线粒体的明显积累，伴有特征性染色体不平衡和相对较少的“驱动”突变。ChRCC和嗜酸细胞瘤（与ChRCC具有相同病理特征的良性肾肿瘤）的代谢组学分析揭示了这些肿瘤类型之间的相似性和差异，主成分分析（PCA）显示出明显的分离。与邻近的正常肾脏相比，ChRCC的谷胱甘肽补救途径（也称为γ-谷氨酰循环）的中间产物显著减少，糖酵解和磷酸戊糖途径中间产物也发生显著变化。我们还发现，γ-谷氨酰循环的关键酶γ-谷氨酰转移酶1（GGT 1）在ChRCC中的表达水平比正常肾脏低100倍，而在透明细胞RCC（ccRCC）中没有发现GGT 1表达的变化。在ChRCC与ccRCC中发现特定代谢物丰度的显著差异，包括氧化应激标志物酞酸盐。GGT 1的下调增强了对氧化应激的敏感性，并与谷胱甘肽途径代谢物的变化相关的丁硫氨酸亚砜亚胺（BSO）治疗。这些数据表明，谷胱甘肽补救途径的损害，与增强的氧化应激，可能有关键的治疗意义，这种罕见的肿瘤类型，目前没有具体的靶向治疗。
The mechanisms of chromophobe renal cell carcinoma (ChRCC) pathogenesis remain a key knowledge gap. Through metabolomics, this study uncovered a fundamental metabolic mechanism underlying the pathogenesis of ChRCC, with key therapeutic implications for this rare tumor type, for which there are currently no specific targeted therapies. Further understanding of the impact of glutathione salvage pathway on mitochondrial function, tumor progression, and targeted therapy can provide insight into other cancers characterized by aberrant glutathione salvage pathway. Chromophobe renal cell carcinoma (ChRCC) accounts for 5% of all sporadic renal cancers and can also occur in genetic syndromes including Birt–Hogg–Dube (BHD) and tuberous sclerosis complex (TSC). ChRCC has a distinct accumulation of abnormal mitochondria, accompanied by characteristic chromosomal imbalances and relatively few “driver” mutations. Metabolomic profiling of ChRCC and oncocytomas (benign renal tumors that share pathological features with ChRCC) revealed both similarities and differences between these tumor types, with principal component analysis (PCA) showing a distinct separation. ChRCC have a striking decrease in intermediates of the glutathione salvage pathway (also known as the gamma-glutamyl cycle) compared with adjacent normal kidney, as well as significant changes in glycolytic and pentose phosphate pathway intermediates. We also found that gamma glutamyl transferase 1 (GGT1), the key enzyme of the gamma-glutamyl cycle, is expressed at ∼100-fold lower levels in ChRCC compared with normal kidney, while no change in GGT1 expression was found in clear cell RCC (ccRCC). Significant differences in specific metabolite abundance were found in ChRCC vs. ccRCC, including the oxidative stress marker ophthalmate. Down-regulation of GGT1 enhanced the sensitivity to oxidative stress and treatment with buthionine sulfoximine (BSO), which was associated with changes in glutathione-pathway metabolites. These data indicate that impairment of the glutathione salvage pathway, associated with enhanced oxidative stress, may have key therapeutic implications for this rare tumor type for which there are currently no specific targeted therapies.
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影响因子：
81.5
作者：
Henske, Elizabeth P.;Jozwiak, Sergiusz;Thiele, Elizabeth A.
通讯作者：
Thiele, Elizabeth A.
影响因子：
5.6
作者：
Paner, Gladell P.;Amin, Mahul B.;Lyles, Robert H.
通讯作者：
Lyles, Robert H.
影响因子：
11.5
作者：
Mayr, Johannes A.;Meierhofer, David;Kofler, Barbara
通讯作者：
Kofler, Barbara
DOI：
10.1165/rcmb.2014-0379rc
发表时间：
2015-07-01
影响因子：
6.4
作者：
Priolo, Carmen;Ricoult, Stephane J. H.;Henske, Elizabeth P.
通讯作者：
Henske, Elizabeth P.
影响因子：
4.7
作者：
Simonnet, H;Demont, J;Godinot, C
通讯作者：
Godinot, C