Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer.
Metabolic enzyme LDHA activates Rac1 GTPase as a noncanonical mechanism to promote cancer.
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DOI：
10.1038/s42255-022-00708-4
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发表时间：
2022-12
影响因子：
20.8
通讯作者：
Feng, Zhaohui
中科院分区：
文献类型：
--
作者：
Liu, Juan;Zhang, Cen;Zhang, Tianliang;Chang, Chun-Yuan;Wang, Jianming;Bazile, Ludvinna;Zhang, Lanjing;Haffty, Bruce G. G.;Hu, Wenwei;Feng, Zhaohui
糖酵解酶乳酸脱氢酶A（LDHA）在癌症中经常过表达，其促进糖酵解和癌症。LDHA的致癌作用归因于其糖酵解酶活性。在这里，我们报告了一个意想不到的LDHA非经典致癌机制; LDHA激活小GTdR Rac 1促进癌症独立于其糖酵解酶活性。从机制上讲，LDHA与Rac 1的活性形式Rac 1-GTP相互作用，抑制Rac 1-GTP与其负调节因子GTP酶激活蛋白的相互作用，导致癌细胞和小鼠组织中的Rac 1激活。在临床乳腺癌标本中，LDHA过表达与较高的Rac 1活性相关。Rac 1抑制显著抑制LDHA的致癌作用。小分子抑制剂对LDHA酶活性和Rac 1活性的联合抑制显示出对LDHA过表达的乳腺癌的协同抑制作用。这些结果揭示了LDHA的一个重要致癌机制，并提出了一个有前途的治疗策略与LDHA过表达的乳腺癌。Liu等人确定了乳酸脱氢酶A（LDHA）促进癌症进展的非代谢机制。这项研究表明，LDHA，独立于其酶活性，直接相互作用，并激活Rac 1
The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here, we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition significantly suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression. Liu et al. identify a non-metabolic mechanism through which lactate dehydrogenase A (LDHA) promotes cancer progression. This study shows that LDHA, independently of its enzymatic activity, directly interacts with and activates Rac1
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影响因子：
56.9
作者：
Joneson, T;White, MA;BarSagi, D
通讯作者：
BarSagi, D
影响因子：
64.5
作者：
Fukata, M;Watanabe, T;Kaibuchi, K
通讯作者：
Kaibuchi, K
FOXM1 通过 LDHA 表达的反式激活促进瓦尔堡效应和胰腺癌进展。
DOI：
10.1158/1078-0432.ccr-13-2407
发表时间：
2014-05-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cui J;Shi M;Xie D;Wei D;Jia Z;Zheng S;Gao Y;Huang S;Xie K
通讯作者：
Xie K
影响因子：
1.9
作者：
Baik, Matthew;French, Barbara;Diaz, Begona
通讯作者：
Diaz, Begona
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ