Endocrine Abstracts

Adrenocortical carcinoma (ACC) is a rare tumour with a poor prognosis. There are a lack of successful targeted therapies and an urgent need to explore novel therapeutic avenues for ACC ¹. In other cancer types, there has been some success in exploiting lipid metabolism. One example is manipulating intracellular cholesterol levels to starve cancer cells. ² Another possibility is targeting the ligand-dependent nuclear receptors Liver-X receptors (LXRab), which act as master regulators of lipid metabolism.³ Despite the potential for beneficial effects of LXR therapies, the complexity of LXR signalling (e.g. LXRb-regulates cholesterol efflux via ABCA1 and APOE and LXRa regulates lipogenesis via SREBP1, FAS), this has in part hindered systemic LXR therapies due to potential adverse effects due to hepatic lipogenesis. The recent development of non-lipogenic selective ABCA1 inducers, which target cholesterol efflux pathways, poses an attractive alternative approach.⁴ In this study, we used the ACC cell line H295R, in 2D and 3D culture models, to test the effects of the ABCA1 inducer CL2-57 on adrenal ABCA1 gene expression, cancer cell viability and migration. Treatment with 1uM CL2-57 led to 5.7-fold induction of ABCA1 expression (P<0.001) with markedly less induction of lipogenic genes (SREBP1, FAS) when compared to pan-LXR agonist, GW3965 (1uM). These effects were retained in the H295R 3D spheroid model. CL2-57 did not affect ACC cell viability, but there was significant reduction in ACC cell migration using wound scratch assays with CL2-57 (P<0.01). This study provides valuable insight into the effects targeting cholesterol efflux pathways in ACC cells using CL2-57 and this is associated with reduced cancer cell migration, supporting use in ACC therapy. Understanding the impact of LXR pathways in ACC may help in developing new treatment approaches to address the challenge of ACC cancer progression.