J Cancer 2017; 8(15):3086-3098. doi:10.7150/jca.14835

Research Paper

Dihydroorotate dehydrogenase Inhibitors Target c-Myc and Arrest Melanoma, Myeloma and Lymphoma cells at S-phase

Mathura Subangari Dorasamy1, 2, Bhavesh Choudhary2, Kavitha Nellore3, Hosahalli Subramanya3, Pooi-Fong Wong1✉

1. Department of Pharmacology, Faculty of Medicine, 50603 University of Malaya, Kuala Lumpur, Malaysia;
2. Aurigene Discovery Technologies Limited, Bollaram Road, Miyapur Hyderabad - 500049, Telangana, India;
3. Aurigene Discovery Technologies Limited, 39-40, KIADB Industrial Area, Phase II Electronic City, Hosur Road, Bangalore - 560100 Karnataka, India.

Abstract

Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme in the de novo biosynthesis pathway of pyrimidines. Inhibition of this enzyme impedes cancer cell proliferation but the exact mechanisms of action of these inhibitors in cancer cells are poorly understood. In this study, we showed that cancer cells, namely melanoma, myeloma and lymphoma overexpressed DHODH protein and treatment with A771726 and Brequinar sodium resulted in cell cycle arrest at S-phase. Transfection with DHODH shRNA depleted DHODH protein expression and impeded the proliferation of melanoma cells. shRNA knockdown of DHODH in combination with DHODH inhibitors further reduced the cancer cell proliferation, suggesting that knockdown of DHODH had sensitized the cells to DHODH inhibitors. Cell cycle regulatory proteins, c-Myc and its transcriptional target, p21 were found down- and up-regulated, respectively, following treatment with DHODH inhibitors in melanoma, myeloma and lymphoma cells. Interestingly, knockdown of DHODH by shRNA had also similarly affected the expression of c-Myc and p21 proteins. Our findings suggest that DHODH inhibitors induce cell cycle arrest in cancer cells via additional DHODH-independent pathway that is associated with p21 up-regulation and c-Myc down-regulation. Hence, DHODH inhibitors can be explored as potential therapeutic agents in cancer therapy.

Keywords: A771726, Brequinar, Ramos, DHODH shRNA, p21.

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How to cite this article:
Dorasamy MS, Choudhary B, Nellore K, Subramanya H, Wong PF. Dihydroorotate dehydrogenase Inhibitors Target c-Myc and Arrest Melanoma, Myeloma and Lymphoma cells at S-phase. J Cancer 2017; 8(15):3086-3098. doi:10.7150/jca.14835. Available from http://www.jcancer.org/v08p3086.htm