The prolyl isomerase Pin1 regulates the NF-kappaB signaling pathway and interleukin-8 expression in glioblastoma.
The brain tumor glioblastoma (GBM) remains one of the most aggressive and devastating tumors despite decades of effort to find more effective treatments. A hallmark of GBM is the constitutive activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling pathway, which regulates cell proliferation, inflammation, migration and apoptosis. The prolyl isomerase, Pin1, has been found to bind directly to the NF-kappaB protein, p65, and cause increases in NF-kappaB promoter activity in a breast cancer model. We now present evidence that this interaction occurs in GBM and that it has important consequences on NF-kappaB signaling. We demonstrate that Pin1 levels are enhanced in primary GBM tissues compared with controls, and that this difference in Pin1 expression affects the migratory capacity of GBM-derived cells. Pin1 knockdown decreases the amount of activated, phosphorylated p65 in the nucleus, resulting in inhibition of the transcriptional program of the IL-8 gene. Through the use of microarray, we also observed changes in the expression levels of other NF-kappaB regulated genes due to Pin1 knockdown. Taken together, these data suggest that Pin1 is an important regulator of NF-kappaB in GBM, and support the notion of using Pin1 as a therapeutic target in the future.
Atkinson
G P
GP
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
Nozell
S E
SE
Harrison
D K
DK
Stonecypher
M S
MS
Chen
D
D
Benveniste
E N
EN
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D055029:Inverted Repeat Sequences; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013752:Tetracycline / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism
D016209:Interleukin-8; D016328:NF-kappa B; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012333:RNA, Messenger; D051996:Transcription Factor RelA; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D013752:Tetracycline