The prolyl isomerase Pin1 regulates the NF-κB signaling pathway and interleukin-8 expression in glioblastoma

Abstract

The brain tumor glioblastoma remains one of the most aggressive and devastating tumors despite decades of effort to find more effective treatments. A hallmark of glioblastoma is the constitutive activation of the NF-κB signaling pathway, which regulates cell proliferation, inflammation, migration, and apoptosis. The prolyl isomerase Pin1 has been found to bind directly to the NF-κB protein, p65, and cause increases in NF-κB promoter activity in a breast cancer model. We now present evidence that this interaction occurs in glioblastoma and that it has important consequences on NF-κB signaling. We demonstrate that Pin1 levels are enhanced in primary glioblastoma tissues compared to controls, and that this difference in Pin1 expression affects the migratory capacity of glioblastoma-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-κB regulated genes due to Pin1 knockdown. Taken together, these data suggest that Pin1 is an important regulator of NF-κB in glioblastoma, and support the notion of using Pin1 as a therapeutic target in the future.

PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

“…expression (Atkinson et al 2009). Similarly, NF-κB activation in PIN1-overexpressing chondrocytes is associated with overproduction of proinflammatory mediators in RA progression (Jeong HG et al 2009).…”

Role of Pin1 Protein in the Pathogenesis of Nonalcoholic Steatohepatitis in a Rodent Model

“…Taking the increased expression of Pin1 in the fed state into account, we can reasonably speculate that altered expressions of Pin1 in accordance with nutrient conditions may be physiologically beneficial. However, Pin1 is also reportedly involved in activations of NF-B and IRAK1, key regulators of cytokine production (19,(22)(23)(24)(25), suggesting the involvement of Pin1 in some inflammatory diseases.…”

Knockdown of Pin1 leads to reduced angiogenic potential and tumorigenicity in glioblastoma cells

“…Pin1 is a novel regulator, which functions at the center of a number of important signaling pathways that are vital for cell growth, differentiation, division and survival (14,15). Pin1 is expressed at varying levels in different cell types and pathological conditions, which indicates a function that is fine-tuned to specific cell types.…”