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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

Downregulation of CIP2A leads to decrease of phosphorylated Akt in lung cancer cells.(A): A549 cells were transfected with NC or CIP2A-specific siRNA for 72 h, and the expression of indicated proteins were detected using Western blots. (B and C): A549 (B) and H1975 cells (C) were treated with rabdocoetsin B (RdB) at indicated concentrations for 48 and 24 h, respectively, and Western blots were performed to analyze the expression of proteins indicated. (D and E): H1975 (D) and A549 (E) cells were treated with rabdocoetsin B (RdB) for indicated time points, and Western blot analysis was carried out with antibodies specific for the indicated proteins. β-actin is used as a loading control.
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pone-0020159-g005: Downregulation of CIP2A leads to decrease of phosphorylated Akt in lung cancer cells.(A): A549 cells were transfected with NC or CIP2A-specific siRNA for 72 h, and the expression of indicated proteins were detected using Western blots. (B and C): A549 (B) and H1975 cells (C) were treated with rabdocoetsin B (RdB) at indicated concentrations for 48 and 24 h, respectively, and Western blots were performed to analyze the expression of proteins indicated. (D and E): H1975 (D) and A549 (E) cells were treated with rabdocoetsin B (RdB) for indicated time points, and Western blot analysis was carried out with antibodies specific for the indicated proteins. β-actin is used as a loading control.

Mentions: In hepatocellular carcinoma cells, CIP2A up-regulates phospho-Akt (pAkt) and decreases Akt-related PP2A activity, whereas silencing CIP2A re-activates PP2A [15]. Since Akt is constitutively active in lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation [16], [17], we examined the effect of CIP2A on pAkt in lung cancer. We showed that CIP2A silencing by specific siRNA resulted in down-regulation of pAkt but not pERK, PCNA, β-catenin, EGFR or Src (Figure 5A). We then investigated whether rabdocoetsin B could modulate the expression of pAkt, and found that treatment with rabdocoetsin B at 5 to 10 µM also down-regulated pAkt in A549 (Figure 5B) and H1975 (Figure 5C) cells. We further showed that in H1975 cells upon rabdocoetsin B at 10 µM, CIP2A was markedly downregulated in 6 to 12 h and became undetectable in 48 h (Figure 5D), while pAKT was decreased in 18 h (Figure 5D). These results were confirmed in A549 cells treated with rabdocoetsin B (Figure 5E), indicating that this compound can inhibit the CIP2A-Akt pathway in lung cancer.


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)

Downregulation of CIP2A leads to decrease of phosphorylated Akt in lung cancer cells.(A): A549 cells were transfected with NC or CIP2A-specific siRNA for 72 h, and the expression of indicated proteins were detected using Western blots. (B and C): A549 (B) and H1975 cells (C) were treated with rabdocoetsin B (RdB) at indicated concentrations for 48 and 24 h, respectively, and Western blots were performed to analyze the expression of proteins indicated. (D and E): H1975 (D) and A549 (E) cells were treated with rabdocoetsin B (RdB) for indicated time points, and Western blot analysis was carried out with antibodies specific for the indicated proteins. β-actin is used as a loading control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020159-g005: Downregulation of CIP2A leads to decrease of phosphorylated Akt in lung cancer cells.(A): A549 cells were transfected with NC or CIP2A-specific siRNA for 72 h, and the expression of indicated proteins were detected using Western blots. (B and C): A549 (B) and H1975 cells (C) were treated with rabdocoetsin B (RdB) at indicated concentrations for 48 and 24 h, respectively, and Western blots were performed to analyze the expression of proteins indicated. (D and E): H1975 (D) and A549 (E) cells were treated with rabdocoetsin B (RdB) for indicated time points, and Western blot analysis was carried out with antibodies specific for the indicated proteins. β-actin is used as a loading control.
Mentions: In hepatocellular carcinoma cells, CIP2A up-regulates phospho-Akt (pAkt) and decreases Akt-related PP2A activity, whereas silencing CIP2A re-activates PP2A [15]. Since Akt is constitutively active in lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation [16], [17], we examined the effect of CIP2A on pAkt in lung cancer. We showed that CIP2A silencing by specific siRNA resulted in down-regulation of pAkt but not pERK, PCNA, β-catenin, EGFR or Src (Figure 5A). We then investigated whether rabdocoetsin B could modulate the expression of pAkt, and found that treatment with rabdocoetsin B at 5 to 10 µM also down-regulated pAkt in A549 (Figure 5B) and H1975 (Figure 5C) cells. We further showed that in H1975 cells upon rabdocoetsin B at 10 µM, CIP2A was markedly downregulated in 6 to 12 h and became undetectable in 48 h (Figure 5D), while pAKT was decreased in 18 h (Figure 5D). These results were confirmed in A549 cells treated with rabdocoetsin B (Figure 5E), indicating that this compound can inhibit the CIP2A-Akt pathway in lung cancer.

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