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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

CIP2A is over-expressed in human lung cancer.(A): Western blot analysis of CIP2A in human lung cancer cells (A549, H1975, 95D and L78), embryonic lung fibroblast cells (HLF and MRC-5), and normal human bronchial epithelial cells (HBEpiC). (B): Western blot analyses of CIP2A protein in primary lung tumors (T) and adjacent normal lung tissues (N). β-Actin is used as a loading control. Representative results are shown and numbers are referred to individual patients. (C): Western blot analyses of CIP2A protein in inflammatory pseudotumor (P) and adjacent normal lung tissues (N). β-Actin is used as a loading control. (D): Representative images (left panel) and score (right panel) of immunohistochemistry staining for CIP2A expression in primary lung tumors (T) and adjacent normal lung tissues (N). (E): RT-PCR analyses of CIP2A mRNA in primary lung tumors (T) and adjacent normal lung tissues (N). GAPDH is employed as a loading control. Representative results are shown and numbers are referred to individual patients.
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pone-0020159-g001: CIP2A is over-expressed in human lung cancer.(A): Western blot analysis of CIP2A in human lung cancer cells (A549, H1975, 95D and L78), embryonic lung fibroblast cells (HLF and MRC-5), and normal human bronchial epithelial cells (HBEpiC). (B): Western blot analyses of CIP2A protein in primary lung tumors (T) and adjacent normal lung tissues (N). β-Actin is used as a loading control. Representative results are shown and numbers are referred to individual patients. (C): Western blot analyses of CIP2A protein in inflammatory pseudotumor (P) and adjacent normal lung tissues (N). β-Actin is used as a loading control. (D): Representative images (left panel) and score (right panel) of immunohistochemistry staining for CIP2A expression in primary lung tumors (T) and adjacent normal lung tissues (N). (E): RT-PCR analyses of CIP2A mRNA in primary lung tumors (T) and adjacent normal lung tissues (N). GAPDH is employed as a loading control. Representative results are shown and numbers are referred to individual patients.

Mentions: We tested the expression of CIP2A at protein level in nonmalignant and malignant cells, and found that CIP2A was highly expressed in lung cancer cell lines (A549, H1975, 95D and L78) compared to normal human embryonic lung fibroblasts (HLF and MRC5) and normal human bronchial epithelial cells (HBEpiC) (Figure 1A). We then analyzed CIP2A in 60 lung cancer samples from patients came from southern China whose baseline characteristics were listed in Table 1. We showed that CIP2A was over-expressed in 38 (63.3%) tumor specimens assayed by western blotting (Figure 1B). However, in the 60 patient-matched adjacent normal lung tissues, CIP2A was undetectable in 57 (95%) samples, and was weakly expressed in 3 (5%) specimens where its expression was much lower than that in tumor samples of the same patients. In samples from 2 patients with inflammatory pseudotumor, CIP2A was not detected in both the pseudotumor and adjacent lung tissues (Figure 1C). Immunohistochemistry assay confirmed that CIP2A was dramatically elevated with a higher immunoreactivity score in tumor samples in 26 out of 39 patients (66.7%) tested (Figure 1D). At mRNA level, CIP2A was also over-expressed in lung tumor tissues compared to normal lung tissues in 39 of 58 (67.2%) patients tested (Figure 1E). Taken together, CIP2A is dramatically elevated in lung cancer tumor samples compared to paired normal lung tissues.


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)

CIP2A is over-expressed in human lung cancer.(A): Western blot analysis of CIP2A in human lung cancer cells (A549, H1975, 95D and L78), embryonic lung fibroblast cells (HLF and MRC-5), and normal human bronchial epithelial cells (HBEpiC). (B): Western blot analyses of CIP2A protein in primary lung tumors (T) and adjacent normal lung tissues (N). β-Actin is used as a loading control. Representative results are shown and numbers are referred to individual patients. (C): Western blot analyses of CIP2A protein in inflammatory pseudotumor (P) and adjacent normal lung tissues (N). β-Actin is used as a loading control. (D): Representative images (left panel) and score (right panel) of immunohistochemistry staining for CIP2A expression in primary lung tumors (T) and adjacent normal lung tissues (N). (E): RT-PCR analyses of CIP2A mRNA in primary lung tumors (T) and adjacent normal lung tissues (N). GAPDH is employed as a loading control. Representative results are shown and numbers are referred to individual patients.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105001&req=5

pone-0020159-g001: CIP2A is over-expressed in human lung cancer.(A): Western blot analysis of CIP2A in human lung cancer cells (A549, H1975, 95D and L78), embryonic lung fibroblast cells (HLF and MRC-5), and normal human bronchial epithelial cells (HBEpiC). (B): Western blot analyses of CIP2A protein in primary lung tumors (T) and adjacent normal lung tissues (N). β-Actin is used as a loading control. Representative results are shown and numbers are referred to individual patients. (C): Western blot analyses of CIP2A protein in inflammatory pseudotumor (P) and adjacent normal lung tissues (N). β-Actin is used as a loading control. (D): Representative images (left panel) and score (right panel) of immunohistochemistry staining for CIP2A expression in primary lung tumors (T) and adjacent normal lung tissues (N). (E): RT-PCR analyses of CIP2A mRNA in primary lung tumors (T) and adjacent normal lung tissues (N). GAPDH is employed as a loading control. Representative results are shown and numbers are referred to individual patients.
Mentions: We tested the expression of CIP2A at protein level in nonmalignant and malignant cells, and found that CIP2A was highly expressed in lung cancer cell lines (A549, H1975, 95D and L78) compared to normal human embryonic lung fibroblasts (HLF and MRC5) and normal human bronchial epithelial cells (HBEpiC) (Figure 1A). We then analyzed CIP2A in 60 lung cancer samples from patients came from southern China whose baseline characteristics were listed in Table 1. We showed that CIP2A was over-expressed in 38 (63.3%) tumor specimens assayed by western blotting (Figure 1B). However, in the 60 patient-matched adjacent normal lung tissues, CIP2A was undetectable in 57 (95%) samples, and was weakly expressed in 3 (5%) specimens where its expression was much lower than that in tumor samples of the same patients. In samples from 2 patients with inflammatory pseudotumor, CIP2A was not detected in both the pseudotumor and adjacent lung tissues (Figure 1C). Immunohistochemistry assay confirmed that CIP2A was dramatically elevated with a higher immunoreactivity score in tumor samples in 26 out of 39 patients (66.7%) tested (Figure 1D). At mRNA level, CIP2A was also over-expressed in lung tumor tissues compared to normal lung tissues in 39 of 58 (67.2%) patients tested (Figure 1E). Taken together, CIP2A is dramatically elevated in lung cancer tumor samples compared to paired normal lung tissues.

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