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Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy.

Publication ,  Journal Article
Switzer, CH; Cheng, RYS; Vitek, TM; Christensen, DJ; Wink, DA; Vitek, MP
Published in: Oncogene
June 2, 2011

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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Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

June 2, 2011

Volume

30

Issue

22

Start / End Page

2504 / 2513

Location

England

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Transcription Factors
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Peptides
  • Oncology & Carcinogenesis
  • Neoplasms
  • NM23 Nucleoside Diphosphate Kinases
  • Humans
  • Histone Chaperones
 

Citation

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Switzer, C. H., Cheng, R. Y. S., Vitek, T. M., Christensen, D. J., Wink, D. A., & Vitek, M. P. (2011). Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene, 30(22), 2504–2513. https://doi.org/10.1038/onc.2010.622
Switzer, C. H., R. Y. S. Cheng, T. M. Vitek, D. J. Christensen, D. A. Wink, and M. P. Vitek. “Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy.Oncogene 30, no. 22 (June 2, 2011): 2504–13. https://doi.org/10.1038/onc.2010.622.
Switzer CH, Cheng RYS, Vitek TM, Christensen DJ, Wink DA, Vitek MP. Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene. 2011 Jun 2;30(22):2504–13.
Switzer, C. H., et al. “Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy.Oncogene, vol. 30, no. 22, June 2011, pp. 2504–13. Pubmed, doi:10.1038/onc.2010.622.
Switzer CH, Cheng RYS, Vitek TM, Christensen DJ, Wink DA, Vitek MP. Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy. Oncogene. 2011 Jun 2;30(22):2504–2513.

Published In

Oncogene

DOI

EISSN

1476-5594

Publication Date

June 2, 2011

Volume

30

Issue

22

Start / End Page

2504 / 2513

Location

England

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Transcription Factors
  • Signal Transduction
  • Proto-Oncogene Proteins c-akt
  • Peptides
  • Oncology & Carcinogenesis
  • Neoplasms
  • NM23 Nucleoside Diphosphate Kinases
  • Humans
  • Histone Chaperones