Abstract
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 1.3.3.1) 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.
Highlights
As an aggressive and usually fatal malignancy, malignant melanoma (MM) is one of the fastest rising cancer and has a poor prognosis [1]
To explore the mechanisms underlying autophagy induced by DHODH inhibition, we found that AMPK-Ulk1 axis was activated in this process
To explore the effect of DHODH inhibition by leflunomide, we detected cell growth and proliferation by cell counting method, MTT assay and bromo-2 deoxyuridine (Brdu) assay in human melanoma A375 and MV3 cells after treatment of leflunomide
Summary
As an aggressive and usually fatal malignancy, malignant melanoma (MM) is one of the fastest rising cancer and has a poor prognosis [1]. The main treatment of melanoma is surgical resection, but only patients in early stage can be cured [2]. Once it has progressed to the metastatic stage, it remains an incurable disease, with a 5-year survival rate of 16% [3]. Most chemotherapeutics and immunotherapeutics as well as radiotherapeutics have failed to increase survival rates of patients with malignant melanoma [4, 5]. Investigating some novel target therapy with high efficiency for malignant melanoma are problems to be solved. There are significant differences of metabolism within tumor cells [6]
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