CDO1 phosphorylation is required for IL-6-induced tumor cell proliferation through governing cysteine availability

Inflammatory pathways are often hijacked by cancer cells to favor their own proliferation and survival. Cysteine dioxygenase type 1 (CDO1), an iron-dependent thiol dioxygenase enzyme, catalyzes the rate-limiting step for cysteine oxidation, and so that functions as an important regulator of cellular cysteine availability. However, whether inflammatory environment affects CDO1 activity and cysteine oxidation and its potential impact on tumor growth remains substantially elusive. In the present study, we demonstrate that CDO1 activity and cysteine oxidation is inhibited upon IL-6 treatment, without noticeable alterations in CDO1 expression. Mechanistically, AKT1 phosphorylates CDO1 T89 under IL-6 treatment, which represses CDO1 enzymatic activity by disrupting iron incorporation. Further, AKT1-mediated CDO1 T89 phosphorylation is required for IL-6-elicited oral squamous cell carcinoma (OSCC) growth, and is associated with the progression of OSCC development. The present data discover a new mechanism by which AKT1-mediated CDO1 T89 phosphorylation governs cysteine oxidation to support OSCC growth, thereby highlighting its value as a potential anti-tumor target.