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Targeting Inhibitors of the Tumor Suppressor PP2A for the Treatment of Pancreatic Cancer
Open accessAbstract
Pancreatic cancer is a deadly disease that is usually diagnosed in the advanced stages when few effective therapies are available. Given the aggressive clinical course of this disease and lack of good treatment options, the development of new therapeutic agents for the treatment of pancreatic cancer is of the upmost importance. Several pathways that have shown to contribute to pancreatic cancer progression are negatively regulated by the tumor suppressor protein phosphatase 2A (PP2A). Here, the endogenous inhibitors of PP2A, SET (also known as I2PP2A) and cancerous inhibitor of PP2A (CIP2A), were shown to be overexpressed in human pancreatic cancer, contributing to decreased PP2A activity and overexpression and stabilization of the oncoprotein c-Myc, a key PP2A target. Knockdown of SET or CIP2A increases PP2A activity, increases c-Myc degradation, and decreases the tumorigenic potential of pancreatic cancer cell lines both in vitro and in vivo. Moreover, treatment with a novel SET inhibitor, OP449, pharmacologically recapitulates the phenotypes and significantly reduces proliferation and tumorigenic potential of several pancreatic cancer cell lines, with an accompanying attenuation of cell growth and survival signaling. Furthermore, primary cells from patients with pancreatic cancer were sensitive to OP449 treatment, indicating that PP2A-regulated pathways are highly relevant to this deadly disease. Implications: The PP2A inhibitors SET and CIP2A are overexpressed in human pancreatic cancer and are important for pancreatic cancer cell growth and transformation; thus, antagonizing SET and/or CIP2A may be an innovative approach for the treatment of human pancreatic cancer. Mol Cancer Res; 12(6); 924–39. ©2014 AACR.
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“This is a very important finding because the therapeutic effects of inhibition of CIP2A protein expression have been validated by numerous studies [6 -8,10 -12,21].”
From Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56 (2017) · cites this paper as [7]
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Metadata
- Authors
- Farrell, A. S., Allen-Petersen, B., Daniel, C. J., Wang, X., Wang, Z., Rodriguez, S., Impey, S., Oddo, J., Vitek, M. P., Lopez, C., Christensen, D. J., Sheppard, B., & Sears, R. C.
- Affiliations
- Authors' Affiliations: Departments of 1Molecular and Medical Genetics,
- Oregon Health & Science University (US)
- Oncotide Pharmaceuticals (United States) (US)
- Duke Medical Center (US)
- 2Hematology and Oncology, and
- 3Surgery,
- Corresponding author
- Sears, Rosalie C.
- ORCID
- Venue
- Molecular Cancer Research
- Published
- 2014-06-01
- Volume
- 12
- Issue
- 6
- Pages
- 924-939
- ISSN
- 1541-7786 (ISSN-L)
- 1557-3125
- PMC
- PMC4116560
- OpenAlex
- W2108146440
- Cited by
- 114
- References
- 60
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 12 · 2020: 9 · 2019: 11 · 2018: 10 · 2017: 16 · 2016: 11 · 2015: 6 · 2014: 5
- FWCI
- 6.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA129040, R01CA129040, R01CA196228, R41CA165570, R01CA100855, P30CA069533)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- pancreatic cancer, protein phosphatase 2A, CIP2A, c-Myc, PP2A inhibitors, tumor suppressor regulation, c-Myc degradation, tumorigenicity, cell proliferation, cell survival signaling
- MeSH terms
- Animals, Cell Movement, DNA-Binding Proteins, Humans, Pancreatic Neoplasms, Peptides, Transcription Factors, Transfection, Signal Transduction, Gene Expression Regulation, Neoplastic, Mice, SCID, Mice, Inbred NOD, Cell Line, Tumor, Cell Proliferation, Mice, Protein Phosphatase 2, Gene Knockdown Techniques, Histone Chaperones
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