Celastrol induces proteasomal degradation of FANCD2 to sensitize lung cancer cells to DNA crosslinking agents.
Bottom Line: In the present study, we aimed to identify FANCD2-targeting agents, and found that the natural compound celastrol induced degradation of FANCD2 through the ubiquitin-proteasome pathway.Furthermore, celastrol treatment abrogated the G2 checkpoint induced by IR, and enhanced the ICL agent-induced DNA damage and inhibitory effects on lung cancer cells through depletion of FANCD2.These results indicate that celastrol is a FANCD2 inhibitor that could interfere with the monoubiquitination and protein stability of FANCD2, providing a novel opportunity to develop FA pathway inhibitor and combinational therapy for malignant neoplasms.
Affiliation: Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.Show MeSH
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Mentions: We investigated the underlying mechanism of celastrol-induced downregulation of FANCD2. By RT-PCR assay, we showed that treatment with celastrol at 5 μM for 6 h did not perturb FANCD2 expression at mRNA level in A549 cells (Fig.2a). Protein synthesis inhibitor CHX was employed to detect the protein stability of FANCD2. We found that in A549 cells treated with CHX (50 μg/mL) alone, the expression of FANCD2 was not decreased within 6 h (Fig.2b). Interestingly, treatment with CHX in combination with celastrol dramatically decreased FANCD2 at protein level within 4 h (Fig.2b), indicating that celastrol impaired the protein stability of FANCD2 by triggering its degradation.
Affiliation: Division of Molecular Carcinogenesis and Targeted Therapy for Cancer, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.