Immunohistochemical Analysis of the Metabolic Phenotype of Adrenal Cortical Carcinoma

Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (n = 42), adrenal cortical adenoma (ACA; n = 50), and normal adrenal cortical tissue samples (n = 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (p < 0.001 and p = 0.014, respectively) or normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (p = 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (p = 0.003) or normal adrenal cortical tissue samples (p = 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (p < 0.001 and p = 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.