Metabolic characteristics of kidney cancers have mainly been obtained from the most
frequent clear cell renal cell carcinoma (CCRCC) studies. Moreover, the bioenergetic
perturbances that affect metabolic adaptation possibilities of papillary renal cell
carcinoma (PRCC) have not yet been detailed. Therefore, our study aimed to analyze
the in situ metabolic features of PRCC vs. CCRCC tissues and compared the metabolic
characteristics of PRCC, CCRCC, and normal tubular epithelial cell lines. The protein
and mRNA expressions of the molecular elements in mammalian target of rapamycin (mTOR)
and additional metabolic pathways were analyzed in human PRCC cases compared to CCRCC.
The metabolic protein expression pattern, metabolite content, mTOR, and metabolic
inhibitor sensitivity of renal carcinoma cell lines were also studied and compared
with tubular epithelial cells, as “normal” control. We observed higher protein expressions
of the “alternative bioenergetic pathway” elements, in correlation with the possible
higher glutamine and acetate consumption in PRCC cells instead of higher glycolytic
and mTOR activity in CCRCCs. Increased expression of certain metabolic pathway markers
correlates with the detected differences in metabolite ratios, as well. The lower
lactate/pyruvate, lactate/malate, and higher pyruvate/citrate intracellular metabolite
ratios in PRCC compared to CCRCC cell lines suggest that ACHN (PRCC) have lower Warburg
glycolytic capacity, less pronounced pyruvate to lactate producing activity and shifted
OXPHOS phenotype. However, both studied renal carcinoma cell lines showed higher mTOR
activity than tubular epithelial cells cultured in vitro, the metabolite ratio, the
enzyme expression profiles, and the higher mitochondrial content also suggest increased
importance of mitochondrial functions, including mitochondrial OXPHOS in PRCCs. Additionally,
PRCC cells showed significant mTOR inhibitor sensitivity and the used metabolic inhibitors
increased the effect of rapamycin in combined treatments. Our study revealed in situ
metabolic differences in mTOR and metabolic protein expression patterns of human PRCC
and CCRCC tissues as well as in cell lines. These underline the importance in the
development of specific new treatment strategies, new mTOR inhibitors, and other anti-metabolic
drug combinations in PRCC therapy.
