Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer.
Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer.
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天然存在的脱酰磷酸异构酶是癌症细胞选择疗法的有希望的靶标。
DOI：
10.1038/s41598-022-08051-0
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发表时间：
2022-03-07
影响因子：
4.6
通讯作者：
López-Velázquez G
中科院分区：
文献类型：
--
作者：
Enríquez-Flores S;Flores-López LA;De la Mora-De la Mora I;García-Torres I;Gracia-Mora I;Gutiérrez-Castrellón P;Fernández-Lainez C;Martínez-Pérez Y;Olaya-Vargas A;de Vos P;López-Velázquez G
人磷酸丙糖异构酶（HsTIM）是一种中枢糖酵解酶，在糖酵解加速的癌细胞中过表达。三阴性乳腺癌高度依赖糖酵解，通常采用手术、放疗和化疗的组合治疗。脱酰胺的HsTIM最近被提议作为可药物化的靶标。尽管巯基反应性药物影响脱酰胺HsTIM互补细胞的细胞生长，但该蛋白作为选择性靶点的作用尚未得到证实。为了深入研究脱酰胺HsTIM作为选择性靶点的有用性，我们评估了其在乳腺癌细胞中的自然积累。我们发现脱酰胺HsTIM在乳腺癌细胞中积累，但不在非癌细胞中积累。癌细胞被选择性地编程以经历与巯基反应性药物的细胞死亡，所述巯基反应性药物诱导甲基乙二醛（MGO）和晚期糖基化终产物（AGEs）的产生。在体内，硫醇反应性药物有效地抑制异种移植肿瘤的生长，其潜在机制涉及脱酰胺HsTIM。我们的研究结果证明了脱酰胺HsTIM作为靶点的有用性，以开发新的治疗策略，用于治疗癌症和其他病理，其中这种后修饰的蛋白质积累。
Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates.
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影响因子：
4.3
作者：
Allaman I;Bélanger M;Magistretti PJ
通讯作者：
Magistretti PJ
影响因子：
5.9
作者：
Keibler MA;Wasylenko TM;Kelleher JK;Iliopoulos O;Vander Heiden MG;Stephanopoulos G
通讯作者：
Stephanopoulos G
影响因子：
3.6
作者：
LEONCINI, G;MARESCA, M;BUZZI, E
通讯作者：
BUZZI, E
DOI：
10.1073/pnas.1504022112
发表时间：
2015-04-07
影响因子：
11.1
作者：
Harbut, Michael B.;Vilcheze, Catherine;Wang, Feng
通讯作者：
Wang, Feng
影响因子：
--
作者：
Grimsley, Gerald R;Pace, C Nick
通讯作者：
Pace, C Nick