Cited by 172Protein Kinase Regulation and GTPase SignalingMechanisms of cancer metastasisCancer Mechanisms and Therapy

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Targeting SET/I2PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy

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Switzer, C H, Cheng, R Y S, Vitek, T M, Christensen, D J, Wink, D A, Vitek, M P·2011·Oncogene

DOI 10.1038/onc.2010.622PMC PMC3107340

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Abstract

The SET oncoprotein participates in cancer progression by affecting multiple cellular processes, inhibiting the tumor suppressor protein phosphatase 2A (PP2A), and inhibiting the metastasis suppressor nm23-H1. On the basis of these multiple activities, we hypothesized that targeted inhibition of SET would have multiple discrete and measurable effects on cancer cells. Here, the effects of inhibiting SET oncoprotein function on intracellular signaling and proliferation of human cancer cell lines was investigated. We observed the effects of COG112, a novel SET interacting peptide, on PP2A activity, Akt signaling, nm23-H1 activity and cellular migration/invasion in human U87 glioblastoma and MDA-MB-231 breast adenocarcinoma cancer cell lines. We found that COG112 interacted with SET protein and inhibited the association between SET and PP2A catalytic subunit (PP2A-c) and nm23-H1. The interaction between COG112 and SET caused PP2A phosphatase and nm23-H1 exonuclease activities to increase. COG112-mediated increases in PP2A activity resulted in the inhibition of Akt signaling and cellular proliferation. Additionally, COG112 inhibited SET association with Ras-related C(3) botulinum toxin substrate 1 (Rac1), leading to decreased cellular migration and invasion. COG112 treatment releases the SET-mediated inhibition of the tumor suppressor PP2A, as well as the metastasis suppressor nm23-H1. These results establish SET as a novel molecular target and that the inhibition of SET may have beneficial effects in cancer chemotherapy.

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Authors: Switzer, C. H., Cheng, R. Y. S., Vitek, T. M., Christensen, D. J., Wink, D. A., & Vitek, M. P.
Affiliations: National Institutes of Health (US)
Cognosci (United States) (US)
Duke Medical Center (US)
Corresponding author: Wink, D A
Vitek, M P
ORCID: Switzer, C H
Cheng, R Y S
Christensen, D J
Wink, D A
Vitek, M P
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2011-02-07
Volume: 30
Issue: 22
Pages: 2504-2513
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/onc.2010.622
PMC: PMC3107340
OpenAlex: W2021359328
Cited by: 171
References: 50
Citations by year: 2026: 2 · 2025: 6 · 2024: 3 · 2023: 11 · 2022: 12 · 2021: 12 · 2020: 9 · 2019: 10 · 2018: 11 · 2017: 16 · 2016: 15 · 2015: 14 · 2014: 15 · 2013: 14 · 2012: 15
FWCI: 6.49
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Cancer Institute (ZIASC007281, ZIABC010899)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
Keywords: protein phosphatase 2A, nm23-H1, Akt signaling, cell proliferation, cell migration and invasion, Rac1, glioblastoma, breast adenocarcinoma, metastasis suppressor, tumor suppressor gene reactivation, cancer therapy targets
MeSH terms: Antineoplastic Agents, Cell Movement, DNA-Binding Proteins, Humans, Neoplasms, Peptides, Transcription Factors, Signal Transduction, rac1 GTP-Binding Protein, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, NM23 Nucleoside Diphosphate Kinases, Histone Chaperones

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Targeting SET/I2PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy

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