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

Abstract

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.

• Authors: Pei-Li Yao, Liping Chen, Tomasz P Dobrzański, Bokai Zhu, Boo-Hyon Kang, Rolf Müller, Frank J Gonzalez, Jeffrey M Peters
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 56 Issue 5 Pg. 1472-1483 (05 2017) ISSN: 1098-2744 [Electronic] United States
• PMID: 27996177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Published [2016]. This article is a U.S. Government work and is in the public domain in the USA.

Chemical References

• PPAR delta
• PPAR-beta
• Retinoic Acid Receptor alpha
• SOX2 protein, human
• SOXB1 Transcription Factors
• TP53 protein, human
• Tumor Suppressor Protein p53
• Tretinoin
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Animals
• Cell Differentiation (physiology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Female
• Humans
• Mice, Nude
• Neuroblastoma (drug therapy, metabolism, pathology)
• PPAR delta (genetics, metabolism)
• PPAR-beta (genetics, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Retinoic Acid Receptor alpha (metabolism)
• SOXB1 Transcription Factors (metabolism)
• Tretinoin (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)
• Xenograft Model Antitumor Assays