title: Targeting SET/I(2)PP2A oncoprotein functions as a multi-pathway strategy for cancer therapy.
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.
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Switzer
authors.forename: R Y S
authors.initials: RY
authors.lastname: Cheng
authors.forename: T M
authors.initials: TM
authors.lastname: Vitek
authors.forename: D J
authors.initials: DJ
authors.lastname: Christensen
authors.forename: D A
authors.initials: DA
authors.lastname: Wink
authors.forename: M P
authors.initials: MP
authors.lastname: Vitek
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins; D056488:Histone Chaperones / Q000037:antagonists & inhibitors*; D006801:Humans; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D010455:Peptides / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C530207:COG112 peptide; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D054778:NM23 Nucleoside Diphosphate Kinases; D010455:Peptides; C107953:RAC1 protein, human; C513473:SET protein, human; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt; C517938:NME1 protein, human; D020830:rac1 GTP-Binding Protein