Trichostatin A modulates cellular metabolism in renal cell carcinoma to enhance sunitinib sensitivity

Abstract

Although sunitinib is the first-line drug for progressive renal cell carcinoma (RCC), most patients experience its tolerance. One possible way of overcoming drug resistance is combination therapy. Epigenetic modifier is one of the candidate drug group. A recent evidence suggests that cell metabolism is regulated by epigenetic mechanisms. Epigenetic abnormalities lead to changes in metabolism and may contribute to drug resistance and progression of RCC. Consequently, we investigated whether trichostatin A (TSA), a potent histone-deacetylase (HDAC) inhibitor, alters sunitinib-induced cytotoxicity and metabolism in RCC cells at epigenetic regulatory concentrations. Combined metabolome and transcriptome analysis suggested that TSA impacts on energy productive metabolic pathways, such as those involving TCA cycle and nucleotide metabolism especially for increase of hyperphosphorylated form. Combination of sunitinib and TSA increased cell death with PARP cleavage, an early marker of mitochondrial apoptosis, whereas receptor tyrosine kinase signaling, which is the target of sunitinib, was not altered by TSA. Finally, the established sunitinib resistant-RCC cell (786-O Res) was also exposed to sunitinib and TSA combination, resulting in significant growth inhibition. In summary, it was suggested that TSA reduces sunitinib resistance by triggering intracellular metabolome shifts regarding energy metabolism, that is the first recognized mechanism as an HDAC inhibitor.