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 tested the effects of several compounds on the expression of FANCD2, and found that celastrol induced reduction of FANCD2 in a dose- and time-dependent manner. Treatment of A549 cells with celastrol at 5 μM for 6–18 h drastically downregulated FANCD2 at protein level (Fig.1a). Similarly, treatment with celastrol at 1–5 μM for 6 h reduced the expression of FANCD2 in A549 cells (Fig.1a). These observations were confirmed in H1975 cells treated with celastrol (Fig.1b). Celastrol also reduced FANCD2 at protein level in hepatocarcinoma HepG2 cells and breast cancer MCF7 cells (Fig.1c).
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.