PBA preferentially impairs cell survival of glioblastomas carrying mutp53 by reducing its expression level, stabilizing wtp53, downregulating the mevalonate kinase and dysregulating UPR

Abstract

Phenylbutyrate (PBA) is a derivative of Butyric Acid (BA), which has the characteristics of being a histone deacetylase (HDAC) inhibitor and acting as a chemical chaperone. It has the potential to counteract a variety of different diseases, from neurodegeneration to cancer. In this study, we investigated the cytotoxic effect of PBA against glioblastoma cells carrying wt or mutant (mut) p53 and found that it exerted a higher cytotoxic effect against the latter in comparison with the former. This could be due to the downregulation of mutp53, to whose pro-survival effects cancer cells become addicted. In correlation with mutp53 reduction and wtp53 activation, PBA downregulated the expression level of mevalonate kinase (MVK), a key kinase of the mevalonate pathway strongly involved in cancer cell survival. Here we differentiated the chaperoning function of PBA from the others anti-cancer potentiality by comparing its effects to those exerted by NaB, another HDACi that derives from BA but, lacking the phenyl group, cannot act as a chemical chaperone. Interestingly, we observed that PBA induced a stronger cytotoxic effect compared to NaB against U373 cells as it skewed the Unfolded Protein Response (UPR) towards cell death induction, upregulating CHOP and downregulating BIP, and was more efficient in downregulating MVK. The findings of this study suggest that PBA represents a promising molecule against glioblastomas, especially those carrying mutp53, and its use, approved by FDA for urea cycle disorders, should be extended to the glioblastoma anticancer therapy.