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Peroxisome proliferator‐activated receptor‐β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53‐ and SOX2‐mediated cell differentiation

Neuroblastoma is a common childhood cancer typically treated by inducing differentiation with retinoic acid (RA). Peroxisome proliferator‐activated receptor‐β/δ, (PPARβ/δ) is known to promote terminal differentiation of many cell types. In the present study, PPARβ/δ was over‐expressed in three human neuroblastoma cell lines, NGP, SK‐N‐BE(2), and IMR‐32, that exhibit high, medium, and low sensitivity, respectively, to retinoic acid‐induced differentiation to determine if PPARβ/δ and retinoic acid receptors (RARs) could be jointly targeted to increase the efficacy of treatment. All‐trans‐RA (atRA) decreased expression of SRY (sex determining region Y)‐box 2 (SOX2), a stem cell regulator and marker of de‐differentiation, in NGP and SK‐N‐BE(2) cells with inactive or mutant tumor suppressor p53, respectively. However, atRA did not suppress SOX2 expression in IMR‐32 cells carrying wild‐type p53. Over‐expression and/or ligand activation of PPARβ/δ reduced the average volume and weight of ectopic tumor xenografts from NGP, SK‐N‐BE(2), or IMR‐32 cells compared to controls. Compared with that found with atRA, PPARβ/δ suppressed SOX2 expression in NGP and SK‐N‐BE(2) cells and ectopic xenografts, and was also effective in suppressing SOX2 expression in IMR‐32 cells that exhibit higher p53 expression compared to the former cell lines. Combined, these observations demonstrate that activating or over‐expressing PPARβ/δ induces cell differentiation through p53‐ and SOX2‐dependent signaling pathways in neuroblastoma cells and tumors. This suggests that combinatorial activation of both RARα and PPARβ/δ may be suitable as an alternative therapeutic approach for RA‐resistant neuroblastoma patients.