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Celastrol induces proteasomal degradation of FANCD2 to sensitize lung cancer cells to DNA crosslinking agents.

Wang GZ, Liu YQ, Cheng X, Zhou GB - Cancer Sci. (2015)

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.We demonstrated that celastrol downregulated the basal and DNA damaging agent-induced monoubiquitination of FANCD2, followed by proteolytic degradation of the substrate.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.

View Article: PubMed Central - PubMed

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.

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Celastrol induces degradation of FANCD2. (a, b) A549 cells and H1975 cells were treated with celastrol at indicated time points and indicated concentrations, lysed, and Western blotting was performed using anti-FANCD2 and anti-Actin antibodies. (c) Western blot analysis of FANCD2 expression in HepG2 and MCF-7 cells treated with celastrol.
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fig01: Celastrol induces degradation of FANCD2. (a, b) A549 cells and H1975 cells were treated with celastrol at indicated time points and indicated concentrations, lysed, and Western blotting was performed using anti-FANCD2 and anti-Actin antibodies. (c) Western blot analysis of FANCD2 expression in HepG2 and MCF-7 cells treated with celastrol.

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).


Celastrol induces proteasomal degradation of FANCD2 to sensitize lung cancer cells to DNA crosslinking agents.

Wang GZ, Liu YQ, Cheng X, Zhou GB - Cancer Sci. (2015)

Celastrol induces degradation of FANCD2. (a, b) A549 cells and H1975 cells were treated with celastrol at indicated time points and indicated concentrations, lysed, and Western blotting was performed using anti-FANCD2 and anti-Actin antibodies. (c) Western blot analysis of FANCD2 expression in HepG2 and MCF-7 cells treated with celastrol.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520643&req=5

fig01: Celastrol induces degradation of FANCD2. (a, b) A549 cells and H1975 cells were treated with celastrol at indicated time points and indicated concentrations, lysed, and Western blotting was performed using anti-FANCD2 and anti-Actin antibodies. (c) Western blot analysis of FANCD2 expression in HepG2 and MCF-7 cells treated with celastrol.
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).

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.We demonstrated that celastrol downregulated the basal and DNA damaging agent-induced monoubiquitination of FANCD2, followed by proteolytic degradation of the substrate.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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus