Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Receptor protein kinase activation is common in cancers, but its role in ferroptosis is unclear.
• Understanding mechanisms that regulate ferroptosis is crucial for cancer therapy development.

Purpose of the Study:

• To investigate the impact of receptor protein kinase activation on ferroptosis.
• To elucidate the role of creatine kinase B (CKB) in cancer cell survival and ferroptosis regulation.

Main Methods:

• Investigated insulin-like growth factor 1 receptor (IGF-1R) signaling pathway.
• Utilized phosphoproteomic analysis to identify CKB phosphorylation sites.
• Assessed the effect of CKB phosphorylation on GPX4 stability and ferroptosis in vitro and in vivo.
• Correlated CKB and GPX4 phosphorylation levels with patient prognosis in hepatocellular carcinoma.

Main Results:

• AKT-activated IGF-1R signaling phosphorylates CKB at T133, reducing its metabolic activity.
• Phosphorylated CKB binds to and phosphorylates GPX4 at S104, preventing its degradation by chaperone-mediated autophagy.
• CKB-mediated GPX4 stabilization alleviates ferroptosis and promotes tumor growth in mice.
• Elevated CKB and GPX4 phosphorylation levels correlate with poor prognosis in human hepatocellular carcinoma.

Conclusions:

• CKB acts as a protein kinase, stabilizing GPX4 through non-metabolic phosphorylation, thereby inhibiting ferroptosis and promoting cancer progression.
• Targeting the protein kinase activity of CKB presents a potential therapeutic strategy for cancers.
• CKB-mediated GPX4 stabilization is a critical mechanism for tumor cells to counteract ferroptosis.