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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 exhibits anti-tumor activity in lung cancer cells.(A): Lung cancer cells were treated with increasing concentrations of Rabdocoetsin B (RdB) (from 1 µM to 10 µM) and cell viability was measured 48 h by the MTT assay. (B): the IC50 of cells treated with rabdocoetsin B. (C): Rabdocoetsin B induces apoptosis of A549 cells, assayed by flow cytometry. (D and E): Western blots were performed to detect the expression of apoptosis regulators in A549 (D) and H1975 cells (E).
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pone-0020159-g006: Rabdocoetsin B exhibits anti-tumor activity in lung cancer cells.(A): Lung cancer cells were treated with increasing concentrations of Rabdocoetsin B (RdB) (from 1 µM to 10 µM) and cell viability was measured 48 h by the MTT assay. (B): the IC50 of cells treated with rabdocoetsin B. (C): Rabdocoetsin B induces apoptosis of A549 cells, assayed by flow cytometry. (D and E): Western blots were performed to detect the expression of apoptosis regulators in A549 (D) and H1975 cells (E).

Mentions: We evaluated the effects of rabdocoetsin B on lung cancer cells expressing wide-type (WT) or mutant EGFR. We showed that rabdocoetsin B exhibited significant cytotoxic effects on A549, NCI-H1975, HCC827, SPC-A-1, GLC-82, L78 and 95D lung cancer cell lines (Figure 6, A and B). Rabdocoetsin B induced apoptosis of A549 cells (Figure 6C) with activation of casp-8 and casp-9 and cleavage of PARP (Figure 6D). Rabdocoetsin B also caused activation of casp-8 and casp-9 and cleavage of PARP in NCI-H1975 cells (Figure 6E). These results indicate that rabdocoetsin B inhibits proliferation and induces apoptosis of lung cancer cells via activating the endogenous and exogenous apoptosis pathways.


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 exhibits anti-tumor activity in lung cancer cells.(A): Lung cancer cells were treated with increasing concentrations of Rabdocoetsin B (RdB) (from 1 µM to 10 µM) and cell viability was measured 48 h by the MTT assay. (B): the IC50 of cells treated with rabdocoetsin B. (C): Rabdocoetsin B induces apoptosis of A549 cells, assayed by flow cytometry. (D and E): Western blots were performed to detect the expression of apoptosis regulators in A549 (D) and H1975 cells (E).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020159-g006: Rabdocoetsin B exhibits anti-tumor activity in lung cancer cells.(A): Lung cancer cells were treated with increasing concentrations of Rabdocoetsin B (RdB) (from 1 µM to 10 µM) and cell viability was measured 48 h by the MTT assay. (B): the IC50 of cells treated with rabdocoetsin B. (C): Rabdocoetsin B induces apoptosis of A549 cells, assayed by flow cytometry. (D and E): Western blots were performed to detect the expression of apoptosis regulators in A549 (D) and H1975 cells (E).
Mentions: We evaluated the effects of rabdocoetsin B on lung cancer cells expressing wide-type (WT) or mutant EGFR. We showed that rabdocoetsin B exhibited significant cytotoxic effects on A549, NCI-H1975, HCC827, SPC-A-1, GLC-82, L78 and 95D lung cancer cell lines (Figure 6, A and B). Rabdocoetsin B induced apoptosis of A549 cells (Figure 6C) with activation of casp-8 and casp-9 and cleavage of PARP (Figure 6D). Rabdocoetsin B also caused activation of casp-8 and casp-9 and cleavage of PARP in NCI-H1975 cells (Figure 6E). These results indicate that rabdocoetsin B inhibits proliferation and induces apoptosis of lung cancer cells via activating the endogenous and exogenous apoptosis pathways.

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