Endocrine Abstracts

Management of ACC is difficult. Diagnosis usually occurs at an advanced disease stage. Resection of localised disease offers a potential cure, but recurrence is common (75-85% of cases). For the treatment of unresectable/metastatic disease, mitotane is the only approved drug, alongside M-EDP chemotherapy. Mitotane has a narrow therapeutic window and is poorly tolerated. Additionally, ACC is a heterogenous disease regarding phenotype, genotype, disease progression and resistance to mitotane/chemotherapy. Better pre-clinical disease models are necessary to reflect ACC heterogeneity and offer insight into the mechanisms of treatment resistance. Investigating two ACC cell lines, mitotane sensitive H295R and mitotane-resistant MUC-1 demonstrated differing lipid droplet content whereby H295R cells predominantly store cholesteryl esters, while MUC-1 cells stored predominantly triacylglycerol, with an overall similar lipid droplet number in each cell line. Lipid storage may reflect the metabolic needs of each ACC cell line, thus we considered the metabolic and steroidogenic profiles of both cell lines. Seahorse XFe (Agilent) analysis demonstrated that MUC-1 cells rely significantly more on mitochondrial oxidative phosphorylation (OXPHOS) when compared to H295R: in MUC-1, OXPHOS contribution to the cell energy metabolism was 29,62 %, while in H295R 20,97 % (P<0.01). MUC-1 cells demonstrate significantly lower levels of androstenedione and cortisol when compared to H295R cells (P<0.0001). Additionally, MUC-1 cells express significantly lower levels of the steroidogenic enzyme, StaR, compared to H295R cells (P<0.0001) with no appreciable expression of CYP11B1 or CYP11B2 in MUC-1 cells, reflecting a difference in mitochondrial function between both cell lines. Overall, these results complement our previous findings in relation to TAG storage in MUC-1 cells and suggest that these cells use fatty acids derived from TAG lipolysis to fuel mitochondrial respiration through β-oxidation. Recent evidence shows that aggressive cancer cells can rely both on glycolysis and OXPHOS, and that the replenishment of the tricarboxylic acid cycle (TCA) intermediates can support many aspects tumor progression, including drug resistance. Therefore, we propose further investigation to better understand and overcome treatment-resistance in ACC.