GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.
GSTP1 Is a Driver of Triple-Negative Breast Cancer Cell Metabolism and Pathogenicity.
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DOI：
10.1016/j.chembiol.2016.03.017
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发表时间：
2016-05-19
影响因子：
8.6
通讯作者：
Nomura DK
中科院分区：
文献类型：
--
作者：
Louie SM;Grossman EA;Crawford LA;Ding L;Camarda R;Huffman TR;Miyamoto DK;Goga A;Weerapana E;Nomura DK
乳腺癌具有从根本上改变的代谢，从而增强其致病性。虽然已经确定了许多乳腺癌的代谢驱动因素，但介导乳腺癌恶性程度和预后不良的代谢途径尚不清楚。在这里，我们使用基于反应性的化学蛋白质组学平台来分析与预后不良相关的乳腺癌细胞类型中富集的代谢酶，包括三阴性乳腺癌（TNBC）细胞和经历了上皮-间充质转化样恶性程度升高状态的乳腺癌细胞。我们将谷胱甘肽-S-转移酶Pi 1（GSTP 1）鉴定为一种新型TNBC靶标，其通过激活甘油醛-3-磷酸脱氢酶活性的蛋白质相互作用调节糖酵解和脂质代谢、能量学和致癌信号传导途径来控制癌症致病性。我们表明，GSTP 1的遗传或药理学失活损害TNBC细胞中的细胞存活和肿瘤发生。我们提出了GSTP 1抑制剂作为一种新的治疗策略，通过损害关键的癌症代谢和信号通路来对抗TNBC。使用基于反应性的化学蛋白质组学平台，Louie等人已经将GST P1鉴定为三阴性乳腺癌靶标，当其被抑制时，通过抑制GAPDH活性以及下游代谢和信号传导途径来损害乳腺癌致病性。
Breast cancers possess fundamentally altered metabolism that fuels their pathogenicity. While many metabolic drivers of breast cancers have been identified, the metabolic pathways that mediate breast cancer malignancy and poor prognosis are less well understood. Here, we used a reactivity-based chemoproteomic platform to profile metabolic enzymes that are enriched in breast cancer cell-types linked to poor prognosis, including triple-negative breast cancer (TNBC) cells and breast cancer cells that have undergone an epithelial-mesenchymal transition-like state of heightened malignancy. We identified glutathione-S-transferase Pi 1 (GSTP1) as a novel TNBC target that controls cancer pathogenicity by regulating glycolytic and lipid metabolism, energetics, and oncogenic signaling pathways through a protein interaction that activates glyceraldehyde-3-phosphate dehydrogenase activity. We show that genetic or pharmacological inactivation of GSTP1 impairs cell survival and tumorigenesis in TNBC cells. We put forth GSTP1 inhibitors as a novel therapeutic strategy for combatting TNBCs through impairing key cancer metabolism and signaling pathways. Using a reactivity-based chemoproteomic platform, Louie et al. have identified GSTP1 as a triple-negative breast cancer target that, when inhibited, impairs breast cancer pathogenicity through inhibiting GAPDH activity and downstream metabolism and signaling pathways.