Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma

Zhi-Zhou Shi; Xin Jin; Wen-Ting Li; Hao Tao; Sheng-Jie Song; Ze-Wen Fan; Wen Jiang; Jian-Wei Liang; Jie Bai

doi:10.21037/tcr-23-136

Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma

Transl Cancer Res. 2023 Sep 30;12(9):2294-2307. doi: 10.21037/tcr-23-136. Epub 2023 Sep 20.

Authors

Zhi-Zhou Shi^#¹, Xin Jin^#¹, Wen-Ting Li^#¹, Hao Tao¹, Sheng-Jie Song¹, Ze-Wen Fan¹, Wen Jiang², Jian-Wei Liang³, Jie Bai¹

Affiliations

¹ Medical School, Kunming University of Science and Technology, Kunming, China.
² Department of Thoracic Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
³ Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

^# Contributed equally.

Abstract

Background: Ferroptosis is defined as an iron-dependent non-apoptotic form of programmed cell death. Dihydroorotate dehydrogenase (DHODH) is a newly discovered anti-ferroptosis molecule independent from the well-known GPX4 and AIFM2. However, the expression pattern and especially the functional roles of DHODH during cancer cell death are generally unknown.

Methods: The databases of Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, and Tumor Immune Estimation Resource (TIMER), and methods of colony formation, Cell Counting Kit-8 (CCK-8), adenosine triphosphate (ATP) detection, RNA-seq, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting were used to analyze the expression level, prognostic role, and oncogenic roles of DHODH in cancers.

Results: DHODH overexpression was identified in many types of cancers including esophageal carcinoma (ESCA), colon adenocarcinoma (COAD), rectum adenocarcinoma (READ), and so on. Silence and inactivation of DHODH decreased the abilities of cell proliferation, colony formation, and cellular ATP levels both in esophageal squamous cell carcinoma (ESCC) and colorectal cancer (CRC) cells. Z-VAD-FMK (an apoptosis inhibitor) partially rescued blockade of DHODH-induced death of ESCC cells, and ferroptosis inhibitors (ferrostatin-1 and liproxstatin-1) together with the necroptosis inhibitor (necrostatin-1) partially rescued inhibition of DHODH-induced death of CRC cells, respectively. Pathways including rheumatoid arthritis, salmonella infection, cytokine-cytokine receptor interaction, pertussis, and nuclear factor-κB (NF-κB) were enriched in DHODH-silenced ESCC cells.

Conclusions: Overexpression of DHODH augments cell proliferation and suppresses cell death in ESCC and CRC, and DHODH might be developed as a potential anticancer target.

Keywords: Ferroptosis; apoptosis; colorectal carcinoma; dihydroorotate dehydrogenase (DHODH); esophageal squamous cell carcinoma (ESCC).