Overexpression and Small Molecule-Triggered Downregulation of CIP2A in Lung Cancer
Open accessAbstract
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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The therapeutic effect of inhibition of CIP2A protein expression in tumor growth has been validated by numerous studies.
“The therapeutic effect of inhibition of CIP2A protein expression in tumor growth has been recently validated by numerous studies [10,14 -18].”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [16]
The Results section reports that CIP2A-specific siRNA significantly inhibited growth of lung-cancer xenografts in mice. But the paper describes CIP2A as a *potential* therapeutic target and says the therapeutic potential of CIP2A-targeting agents warrants further investigation; it does not establish a validated therapeutic effect in patients. (LLM, conf=0.83)
Experimental — accuracy not yet measuredTargeting CIP2A binding to B56 could constitute a first structure-based strategy for therapeutic inhibition of CIP2A protein stability and activity.
“As functional consequences of high CIP2A protein expression on tumorigenesis are very well established in numerous recent studies [10,14 -18], it is conceivable that targeting of CIP2A binding to B56 could constitute a first structure-based strategy for therapeutic inhibition of CIP2A protein stability and activity.”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [16]
Inhibition of L533E mutant expression correlated with significantly lower capacity to support expression of the CIP2A target pAkt compared to WT CIP2A.
“Furthermore, inhibition of L533E mutant expression correlated very well with significantly lower capacity to support expression of a well-established CIP2A target pAkt [9,16], as compared to WT CIP2A (Fig 5K and L).”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [16]
CIP2A promotes phosphorylation and activity of both MYC and Akt.
“CIP2A has been shown to promote phosphorylation and activity of both of these critical PP2A targets [6,9,10,12,16]”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [16]
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- Authors
- Ma, L., Wen, Z.-S., Liu, Z., Hu, Z., Ma, J., Chen, X.-Q., Liu, Y.-Q., Pu, J.-X., Xiao, W.-L., Sun, H.-D., & Zhou, G.-B.
- Affiliations
- University of Science and Technology of China (CN)
- Chinese Academy of Sciences (CN)
- Sun Yat-sen University (CN)
- Kunming Institute of Botany (CN)
- Corresponding author
- Sun, Han-Dong
- Zhou, Guang-Biao
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-05-31
- Volume
- 6
- Issue
- 5
- Pages
- e20159
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3105001
- OpenAlex
- W2052790706
- Cited by
- 96
- References
- 28
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 7 · 2020: 1 · 2019: 6 · 2018: 7 · 2017: 9 · 2016: 12 · 2015: 9 · 2014: 13 · 2013: 9 · 2012: 12
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (2010CB529201, 2009ZX09103, KSCX1-YW-R-26, KSCX2-YW-R-235, 81071930, 30871110)
- Chinese Academy of Sciences (KSCX2-YW-R-235, KSCX2-YW-R, KSCX1-YW-R-26, 2010CB529201, 81071930)
- Turun Yliopisto
- Directorate for Biological Sciences
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- CIP2A, lung cancer, protein phosphatase 2A inhibition, oncoprotein overexpression, small molecule drug targets, AKT pathway, cigarette smoking, cell proliferation, apoptosis, siRNA knockdown
- MeSH terms
- Autoantigens, Diterpenes, Humans, Immunohistochemistry, Lung Neoplasms, Membrane Proteins, Smoking, Blotting, Western, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Proto-Oncogene Proteins c-akt, In Vitro Techniques
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