Identification of human LDHC4 as a potential target for anticancer drug discovery |
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| Authors: | Hong Tan Huali Wang Jinhu Ma Hui Deng Qinghua He Qiang Chen Qinglian Zhang |
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| Affiliation: | 1. The Research Institute of Qinghai-Tibet Plateau, Southwest Minzu University, Chengdu 610041, China;2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China;3. School of Laboratory Medicine, Chengdu Medical College, Chengdu 610500, China;4. Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu 610041, China |
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| Abstract: | One of the distinct hallmarks of cancer cells is aerobic glycolysis (Warburg effect). Lactate dehydrogenase A (LDHA) is thought to play a key role in aerobic glycolysis and has been extensively studied, while lactate dehydrogenase C (LDHC), an isoform of LDHA, has received much less attention. Here we showed that human LDHC was significantly expressed in lung cancer tissues, overexpression of Ldhc in mice could promote tumor growth, and knock-down of LDHC could inhibit the proliferation of lung cancer A549 cells. We solved the first crystal structure of human LDHC4 and found that the active-site loop of LDHC4 adopted a distinct conformation compared to LDHA4 and lactate dehydrogenase B4 (LDHB4). Moreover, we found that (ethylamino) (oxo)acetic acid shows about 10 times selective inhibition against LDHC4 over LDHA4 and LDHB4. Our studies suggest that LDHC4 is a potential target for anticancer drug discovery and (ethylamino) (oxo)acetic acid provides a good start to develop lead compounds for selective drugs targeting LDHC4. |
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| Keywords: | Anticancer target Warburg effect LDHC4 structure (Ethylamino) (oxo)acetic acid LDH isoforms Lung cancer Tissue microarray |
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