DHODH inhibition suppresses cutaneous squamous cell carcinoma growth by the induction of differentiation through perturbation of the cellular redox balance

ABSTRACT: Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, has recently emerged as a therapeutic target in various cancers. We have previously identified a pivotal role of DHODH in initiation of cutaneous squamous cell carcinoma (cSCC), the second most common type of non-melanoma skin cancer. However, the key mechanisms driving the anticancer activity of DHODH inhibition remain unexplored in cSCC. To evaluate the impact of DHODH inhibition on cSCC growth, we employed three complementary approaches: (1) pharmacological inhibition of DHODH in mice bearing xenografts of A431 and SCC13 cells through oral administration of leflunomid (LFN) or PTC299 (PTC), and (2) genetic silencing of DHODH via transduction of cells with a lentiviral vector expressing shRNA targeting DHODH (shDHODH) prior to transplantation into NSG mice. After transplantation of A431 or SCC13 cells and once tumors reached an average volume of 150 to 200 mm3, mice were divided into two groups that receiving either vehicle alone or LFN administrated orally on a daily basis. The same procedure was applied for treatment with PTC299. To further investigate, DHODH expression was downregulated in A431 and SCC13 cells using shDHODH. Cells transduced with shCtrol used as control. Six days after transduction, the cells were subcutaneously engrafted into NSG mice. To investigate the molecular consequences of DHODH inhibition across distinct cSCC models, label-free quantitative proteomic analyses were performed on A431 and SCC13 xenografts treated with LFN or PTC299, as well as on tumors transduced with shDHODH (6 xenografts per group).

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Stephane Claverol  

LAB HEAD: Stephane Claverol

PROVIDER: PXD070860 | Pride | 2026-06-15

REPOSITORIES: Pride