National University Medical Institutes

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPAR-y, a member of this family, is expressed in several human cancers, and both natural and synthetic ligands of PPAR-y have been reported to inhibit cancer cell growth. Interestingly, PPAR-y expression correlated with the clinical course of neuroblastoma diagnosed under the age of one year, where neuroblastoma samples from patients who showed a decrease in their urinary VMA (indicating tumor regression) tended to show high PPAR-y mRNA levels and positive PPAR-y immunostaining. Hence, we embark on a research project to increase PPAR-y activation in neuroblastoma cell lines, with the goal of designing more efficacious cancer therapeutics.

In our model of neuroblastoma cell lines, SHSY5Y is a cell line that is more resistant to 15d-PGJ2 (PPAR-y natural ligand)’s anti-proliferative effect as compared to SH-EP1. We found that such a difference in their responses to 15d-PGJ2 is due to the inactivation of PPAR-y in SHSY5Y, which unlike SH-EP1 which showed increased PPAR-y activity after ligand treatment, remains inactive despite increasing doses of 15d-PGJ2. In line with these findings is the observation that NHE1 protein levels, is repressed in SH-EP1 by 15d-PGJ2 treatment, but not in SHSY5Y. Down-regulation of NHE1 has been previously shown to lead to cancer cells’ growth arrest and sensitization to death stimuli.

Hence, our project aims to investigate reasons accounting for the inactivation of PPAR-y in SHSY5Y, which would then allow for therapeutic intervention that may re-activate PPAR-y in this resistant cell line SHSY5Y. Among possible areas of investigation is the localization of PPAR-y in SHSY5Y and SH-EP1. Studies have shown that PPAR-y may be transported out of the nucleus by activated MEK, which renders it inactive as a nuclear receptor. Also, we would be looking at the phosphorylation status of PPAR-y, as phosphorylation of PPAR-y by ERK1/2 and JNK has been shown to inactivate PPAR-y. We aim to reactivate PPAR-g in SHSY5Y by combined chemotherapy such that SHSY5Y cells would be sensitized to PPAR-y ligands. We would also be investigating if NHE1 repression is a determining factor for anti-cancer effects mediated by PPAR-y ligands.