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Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer.

Ma L, Wen ZS, Liu Z, Hu Z, Ma J, Chen XQ, Liu YQ, Pu JX, Xiao WL, Sun HD, Zhou GB - PLoS ONE (2011)

Bottom Line: Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies.CIP2A overexpression was associated with cigarette smoking.Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.

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.

ABSTRACT

Background: Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear.

Methodology/principal findings: Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.

Conclusions/significance: Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation.

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Related in: MedlinePlus

Rabdocoetsin B induces down-regulation of CIP2A.(A): Structure of rabdocoetsin B. (B): A549 cells were treated with rabdocoetsin B (RdB) at various concentrations for 48 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (C): H1975 cells were treated with rabdocoetsin B at various concentrations for 24 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (D): A549 cells were treated with rabdocoetsin B at various concentrations for 48 h, and the mRNA expression of CIP2A was analyzed using real-time RT-PCR.
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pone-0020159-g004: Rabdocoetsin B induces down-regulation of CIP2A.(A): Structure of rabdocoetsin B. (B): A549 cells were treated with rabdocoetsin B (RdB) at various concentrations for 48 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (C): H1975 cells were treated with rabdocoetsin B at various concentrations for 24 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (D): A549 cells were treated with rabdocoetsin B at various concentrations for 48 h, and the mRNA expression of CIP2A was analyzed using real-time RT-PCR.

Mentions: Our central goal was to identify new drug targets and provide lead compounds for drug development. We screened for CIP2A-targeting small molecules by analyzing their effects on CIP2A expression, and identified a natural compound extracted from a Chinese medicinal herbal Rabdosia coetsa, rabdocoetsin B [13], [14] (Figure 4A), could downregulate CIP2A at protein level at 5 to 20 µM in A549 cells (Figure 4B). In H1975 cells, Rabdocoetsin B also triggered downregulation of CIP2A at 5 to 10 µM (Figure 4C). We analyzed the mechanism of CIP2A down-regulation caused by Rabdocoetsin B, and found that rabdocoetsin B significantly inhibited the transcription of CIP2A in a dose-dependent manner (Figure 4D) assessed by real-time RT-PCR.


Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer.

Ma L, Wen ZS, Liu Z, Hu Z, Ma J, Chen XQ, Liu YQ, Pu JX, Xiao WL, Sun HD, Zhou GB - PLoS ONE (2011)

Rabdocoetsin B induces down-regulation of CIP2A.(A): Structure of rabdocoetsin B. (B): A549 cells were treated with rabdocoetsin B (RdB) at various concentrations for 48 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (C): H1975 cells were treated with rabdocoetsin B at various concentrations for 24 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (D): A549 cells were treated with rabdocoetsin B at various concentrations for 48 h, and the mRNA expression of CIP2A was analyzed using real-time RT-PCR.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105001&req=5

pone-0020159-g004: Rabdocoetsin B induces down-regulation of CIP2A.(A): Structure of rabdocoetsin B. (B): A549 cells were treated with rabdocoetsin B (RdB) at various concentrations for 48 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (C): H1975 cells were treated with rabdocoetsin B at various concentrations for 24 h. Western blots were used to detect the expression of CIP2A protein (upper panel) and CIP2A protein expression were quantified and normalized against β-actin expression (lower panel) (D): A549 cells were treated with rabdocoetsin B at various concentrations for 48 h, and the mRNA expression of CIP2A was analyzed using real-time RT-PCR.
Mentions: Our central goal was to identify new drug targets and provide lead compounds for drug development. We screened for CIP2A-targeting small molecules by analyzing their effects on CIP2A expression, and identified a natural compound extracted from a Chinese medicinal herbal Rabdosia coetsa, rabdocoetsin B [13], [14] (Figure 4A), could downregulate CIP2A at protein level at 5 to 20 µM in A549 cells (Figure 4B). In H1975 cells, Rabdocoetsin B also triggered downregulation of CIP2A at 5 to 10 µM (Figure 4C). We analyzed the mechanism of CIP2A down-regulation caused by Rabdocoetsin B, and found that rabdocoetsin B significantly inhibited the transcription of CIP2A in a dose-dependent manner (Figure 4D) assessed by real-time RT-PCR.

Bottom Line: Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies.CIP2A overexpression was associated with cigarette smoking.Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.

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.

ABSTRACT

Background: Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear.

Methodology/principal findings: Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.

Conclusions/significance: Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation.

Show MeSH
Related in: MedlinePlus