S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines

Abstract

Neuroblastoma is a common pediatric solid tumor that exhibits a striking clinical bipolarity favorable and unfavorable. The survival rate of children with unfavorable neuroblastoma remains low among all childhood cancers. MYCN and MYC play a crucial role in determining the malignancy of unfavorable neuroblastomas, whereas high-level expression of the favorable neuroblastoma genes is associated with a good disease outcome and confers growth suppression of neuroblastoma cells. A small fraction of neuroblastomas harbors TP53 mutations at diagnosis, but a higher proportion of the relapse cases acquire TP53 mutations. In this study, we investigated the effect of S(+)-ibuprofen on neuroblastoma cell lines, focusing on the expression of the MYCN, MYC, AKT, p53 proteins and the favorable neuroblastoma genes in vitro as biomarkers of malignancy. Treatment of neuroblastoma cell lines with S(+)-ibuprofen resulted in a significant growth suppression. This growth effect was accompanied by a marked decrease in the expression of MYC, MYCN, AKT and an increase in p53 expression in neuroblastoma cell lines without TP53 mutation. In addition, S(+)-ibuprofen enhanced the expression of some favorable neuroblastoma genes (EPHB6, CD44) and genes involved in growth suppression and differentiation (EGR1, EPHA2, NRG1 and SEL1L). Gene expression profile and Ingenuity pathway analyses using TP53-mutated SKNAS cells further revealed that S(+)-ibuprofen suppressed molecular pathways associated with cell growth and conversely enhanced those of cell cycle arrest and the unfolded protein response. Collectively, these results suggest that S(+)-ibuprofen or its related compounds may have the potential for therapeutic and/or palliative use for unfavorable neuroblastoma.

Ibuprofen Is Deleterious for the Development of First-Trimester Human Fetal Ovary Ex Vivo

“…Similar to its mechanism of action in cancer cells, we observed that ibuprofen alters both proliferation and cell death in human fetal ovary. At a molecular level, studies in several cell lines have suggested a TP53dependent mechanism of ibuprofen toxicity that also involves an increase in the expression of CDKN1A (also known as p21) (Bonelli et al, 2011;Ikegaki et al, 2014;Janssen et al, 2008;Tsai et al, 2004). We found similar increases in TP53 and CDKN1A expression in the human fetal ovary after exposure to ibuprofen, suggesting that ibuprofen toxicity in the human fetal ovary may use a similar signaling pathway, and may act on molecular targets placed at the crossroad of proliferation and cell death.…”

Ibuprofen and diclofenac treatments reduce proliferation of pancreatic acinar cells upon inflammatory injury and mitogenic stimulation

“…However, preclinical studies demonstrated that NSAIDs are also effective in inhibiting the proliferation of a wide range of cancer cells in vitro, either alone or in combination with other cancer therapies. This is further supported by clinical trials demonstrating that long-term use of NSAIDs, including ibuprofen, significantly reduces the risk of colorectal, breast, lung, prostate and gastric cancer and inhibits proliferation of cancer cells, including glioma, neuroblastoma and bladder cancer cells (Baron and Sandler, 2000;Ulrich et al, 2006;Johnson et al, 2010;Ikegaki et al, 2014;Chai et al, 2015;Fajardo and Piazza, 2015;Leidgens et al, 2015), thus increasing the interest for a novel therapeutic application of these drugs. However, this observation raises the question whether the inhibition of cell proliferation mediated by NSAIDs is also observed in non-malignant cells, with the consequence that the drug treatment results in delayed regeneration of tissues following injury.…”

Prostaglandin E2 promotes MYCN non‐amplified neuroblastoma cell survival via β‐catenin stabilization

“…Inhibition of COX enzymes has been shown to inhibit neuroblastoma cell survival in vitro and to inhibit tumour growth in vivo . Indeed, COX‐2 inhibitors attenuated cell viability in neuroblastoma cells.…”

“…In earlier studies, Rasmuson et al demonstrated that exogenous PGE 2 enhanced viability of MYCN-amplified SK-N-BE(2) neuroblastoma cells, suggesting that PGE 2 is involved in neuroblastoma cell viability independent of amplification of MYCN [4]. Inhibition of COX enzymes has been shown to inhibit neuroblastoma cell survival in vitro [7,42] and to inhibit tumour growth in vivo [5]. Indeed, COX-2 inhibitors attenuated cell viability in neuroblastoma cells.…”