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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

Effects of NNK on CIP2A expression.(A): HBEpiC cells were treated with NNK at various concentrations for indicated time points, and western blot was performed to analyze CIP2A expression. (B): BEAS-2B cells were treated with NNK at indicated concentrations for indicated time points, and western blot was conducted to analyze CIP2A expression. 0.05% and 0.1% DMSO were used as a solvent control corresponding to 5 µΜ and 10 µΜ NNK, respectively.
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pone-0020159-g002: Effects of NNK on CIP2A expression.(A): HBEpiC cells were treated with NNK at various concentrations for indicated time points, and western blot was performed to analyze CIP2A expression. (B): BEAS-2B cells were treated with NNK at indicated concentrations for indicated time points, and western blot was conducted to analyze CIP2A expression. 0.05% and 0.1% DMSO were used as a solvent control corresponding to 5 µΜ and 10 µΜ NNK, respectively.

Mentions: The nitrosamine 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone, or the nicotine-derived nitrosamine ketone (NNK), is a key ingredient of tobacco smoke carcinogen which systemically induces tumors of the lung in rats, mice, and hamsters and also plays a major role in lung carcinogenesis [10], [11]. We then investigated whether NNK could directly induce upregulation of CIP2A or not. To do this, HBEpiC (Figure 2A) and BEAS-2B (Figure 2B) bronchial epithelial cells were exposed to NNK at indicated concentration for indicated time points, lysed, and western blot was performed to analyze the expression of CIP2A. The results showed that treatment with NNK at 0.1 to 10 µM for up to 18 days could not perturb CIP2A expression (Figure 2, A and B). In this study, we did not test the long-term effect of NNK on CIP2A expression in vitro or in vivo.


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)

Effects of NNK on CIP2A expression.(A): HBEpiC cells were treated with NNK at various concentrations for indicated time points, and western blot was performed to analyze CIP2A expression. (B): BEAS-2B cells were treated with NNK at indicated concentrations for indicated time points, and western blot was conducted to analyze CIP2A expression. 0.05% and 0.1% DMSO were used as a solvent control corresponding to 5 µΜ and 10 µΜ NNK, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020159-g002: Effects of NNK on CIP2A expression.(A): HBEpiC cells were treated with NNK at various concentrations for indicated time points, and western blot was performed to analyze CIP2A expression. (B): BEAS-2B cells were treated with NNK at indicated concentrations for indicated time points, and western blot was conducted to analyze CIP2A expression. 0.05% and 0.1% DMSO were used as a solvent control corresponding to 5 µΜ and 10 µΜ NNK, respectively.
Mentions: The nitrosamine 4-(methylnitro-samino)-1-(3-pyridyl)-1-butanone, or the nicotine-derived nitrosamine ketone (NNK), is a key ingredient of tobacco smoke carcinogen which systemically induces tumors of the lung in rats, mice, and hamsters and also plays a major role in lung carcinogenesis [10], [11]. We then investigated whether NNK could directly induce upregulation of CIP2A or not. To do this, HBEpiC (Figure 2A) and BEAS-2B (Figure 2B) bronchial epithelial cells were exposed to NNK at indicated concentration for indicated time points, lysed, and western blot was performed to analyze the expression of CIP2A. The results showed that treatment with NNK at 0.1 to 10 µM for up to 18 days could not perturb CIP2A expression (Figure 2, A and B). In this study, we did not test the long-term effect of NNK on CIP2A expression in vitro or in vivo.

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