Inactivation/deficiency of DHODH induces cell cycle arrest and programed cell death in melanoma
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Lichao Liu1,2,*, Zhen Dong2,*, Qian Lei2, Jie Yang2, Huanrong Hu1, Qian Li1, Yacong Ji1, Leiyang Guo1, Yanli Zhang1, Yaling Liu1 and Hongjuan Cui2
1Department of Dermatology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050000, China
2State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, 400715, China
*These authors contributed equally to this work
Hongjuan Cui, email: [email protected], [email protected]
Yaling Liu, email: [email protected]
Keywords: dihydroorotate dehydrogenase (DHODH), leflunomide, autophagy, BCL-2, melanoma
Received: May 27, 2016 Accepted: July 11, 2017 Published: July 19, 2017
Malignant melanoma (MM) is one of the most malignant tumors and has a very poor prognosis. However, there are no effective drugs to treat this disease. As a kind of iron flavin dependent enzyme, dihydroorotate dehydrogenase (DHODH, EC 18.104.22.168) is the fourth and a key enzyme in the de novo biosynthesis of pyrimidines. Herein, we found that DHODH inactivation/deficiency inhibited melanoma cell proliferation, induced cell cycle arrest at S phase and lead to autophagy in human melanoma cells. Meanwhile, leflunomide treatment induced cell apoptosis and deficiency of DHODH sensitized cells to drug-induced apoptosis in BCL-2 deficient melanoma cells, while not in BCL-2 abundant melanoma cells. Then we found that BCL-2 could rescue apoptosis induced by DHODH inactivation/deficiency. Moreover, BCL-2 also showed to promote cell cycle arrest and to inhibit autophagy induced by leflunomide. To explore the mechanisms underlying autophagy induced by DHODH inhibition, we found that AMPK-Ulk1 axis was activated in this process. Besides, JNK was phosphorylated and activated to phosphorylate BCL-2, which abrogated the interaction between BCL-2 and Beclin1 and then abolished autophagy. Our findings provided evidences for the potential of DHODH used as a drug target for melanoma treatment.
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