ENDOCRINE SOCIETY
OXFORD
Targeting of a New Node in Lipid Metabolism as a Potential Treatment Strategy for ACC
Christopher R LaPensee1 .* D and Gary D Hammer1
1Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI 48106, USA Correspondence: Christopher R LaPensee, PhD, Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 109 Zina Pitcher PI. Ann Arbor, MI 48109, USA. Email: lapensee@med.umich.edu.
Key Words: adrenal, cancer, lipid, cholesterol
Abbreviations: ACC, adrenocortical carcinoma; SOAT1, sterol-O-acyl transferase 1.
Tumors of the adrenal cortex (ACC) are rare and aggressive with low overall survival (1). Complete surgical removal of the ad- renal gland is the main treatment for ACC, but symptoms are usually not found until the cancer is large and metastatic. Only a half of patients are amenable to surgical resection upon diagno- sis. Therapeutic options for the treatment of ACC are limited, with the most common chemotherapy regimen including a com- bination of mitotane, doxorubicin, cisplatin, and/or etoposide. Mitotane is an adrenolytic agent derived from the pesticide di- chlorodiphenyltrichloroethane (DDT), and it is the only pharma- cological approach approved by the U.S. Food and Drug Administration for the treatment of ACC. Although mitotane and chemotherapy are used to treat ACC, the response rates are low, and discontinuation of mitotane-based therapy is com- mon due to serious adverse effects.
Despite over a half century of use, the mechanism of action for mitotane has yet to be completely characterized. Recent studies demonstrate that mitotane dysregulates lipid metabolism (2). Among the cytotoxic mechanisms of mitotane is inhibition of sterol-O-acyl transferase 1 (SOAT1), the enzyme responsible catalyzing the combination of free cholesterol and fatty acids into neutral cholesterol esters. Cholesterol is the precursor of steroid hormones and is stored as an ester in lipid droplets in abundance to meet on-demand needs for steroids. Cholesterol stored in lipid droplets is rapidly hydrolyzed by lipases into free cholesterol that is converted to glucocorticoids during stress adaptation. Prevention of esterification causes an excess of free cholesterol and other fatty acids, which are toxic to many cell types. Given the reliance of adrenocortical cells on high capacity for cholesterol storage to produce large a volume of steroids, it is unsurprising that dysregulation of cholesterol storage by esterifi- cation is cytotoxic. Targeted inhibition of cholesterol esterifica- tion for treatment of ACC has been explored using other highly specific pharmacological inhibitors of SOAT1 (3). Although these studies showed promise in preclinical settings, they failed to demonstrate efficacy in clinical trials (4).
Failure to achieve sufficient dosing levels has been attrib- uted to the low success rate of some compounds that target es- terification of cholesterol for the treatment of ACC. Due to
these limitations and the paucity of targetable signaling path- ways, there exists an unmet need for new drugs or drug com- binations that decrease tumor growth and ultimately increase survival of patients with ACC. In the manuscript titled “Mitotane targets lipid droplets to induce lipolysis in adreno- cortical carcinoma” (5), Warde et al raise the possibility that ACCs differ in their capacity to store and utilize lipids, thereby conferring differential sensitivity to mitotane treatment. To reach this conclusion, the authors performed studies using mitotane-sensitive H295R ACC cells and mitotane-resistant MUC-1 ACC cells. Previous work from this research group determined that concentrations of mitotane sufficient to in- duce toxicity in H295R cells fail to induce cell death in MUC-1 cells (6). Only at supratherapeutic concentrations does mitotane cause cytotoxicity in MUC-1 cells. In this new study, comparison of these cell lines revealed a correl- ation between mitotane responsiveness and modes of lipid storage, with lipid droplets in mitotane-sensitive H295R cells comprising both cholesterol esters and triacylglycerol, where- as mitotane-resistant MUC-1 ACC cells store only triacylgly- cerol, and not cholesterol, in lipid droplets. H295R cells were found to express higher levels of key regulators of cholesterol uptake, storage, and lipolysis, consistent with their depend- ence on the capacity for handling abundant cholesterol flux, which is also hypothesized to underly their sensitivity to mitotane-mediated SOAT1 inhibition at concentrations not toxic to MUC-1 cells. Based on their additional finding that expression lipolytic machinery is enriched in H295R cells and upregulated by mitotane, the authors present data sup- porting the novel concept that mitotane-induced toxicity is also mediated through increased lipid release from intracellu- lar stores by lipolysis. Moreover, they find that the suprather- apeutic concentrations of mitotane required to induce cell death in MUC-1 cells occurs through lipolytic increases in fatty acids, rather than inhibition of esterification or liberation of free cholesterol stores as in H295R cells. Collectively, these findings indicate that dysregulation of lipolysis leading to fatty acid accumulation in response to mitotane confers cytotoxic actions in both ACC cell lines.
The studies by Warde et al expand our understanding lipid flux in adrenocortical cells, and we anticipate more studies that will provide improved resolution of lipid dynamics in the context of ACC. As the authors note, targeting of lipolysis may be an attractive target for the treatment of ACC, but over- all has not been a major area of study in the development of cancer therapeutics. Extensive studies have provided strong evidence for reprogramming of lipid metabolism in cancer. Small molecule compounds which can modulate cell death pathways by targeting lipid metabolism have been used to cancer treatment for several years. For example, targeted dys- regulation of cholesterol metabolism by inhibiting the meval- onate pathway, has proven to be a viable anticancer approach (7). HMG-CoA reductase inhibitors, such as statins, have been the most commonly employed cholesterol metabolism- targeting drugs in clinical studies for cancer treatment. Statins are routinely used to treat mitotane-induced hyper- cholesterolemia in ACC patients, and the combination of mi- totane and statins has been shown to be associated with improved tumor control (8). In vitro studies also demonstrate potentiation of mitotane actions in ACC cells by statins, al- though the underlying mechanisms have not yet been com- pletely elucidated (9). While lipid synthesis inhibitors have shown promising anticancer effects in preclinical studies and early phases of clinical trials, major barriers exist in develop- ing cancer treatment by targeting lipid metabolism, mostly due to incomplete understanding of the mechanisms that regu- late lipid synthesis, storage, utilization, and efflux in cancer cells. A more complete understanding of these processes and the discovery or repurposing of new lipid metabolism-related drug targets could accelerate the development of drugs target- ing lipid flux for cancer therapy. Moreover, this work indi- cates additional aspects of lipid handling that can perhaps be exploited for therapeutic intent in other adrenal diseases in- volving abnormal cholesterol and lipid flux, such as congeni- tal lipoid adrenal hyperplasia, adrenoleukodystrophy, Niemann-Pick disease, cholesterol ester storage disease, and Wolman disease.
Disclosures
G.D.H .: Founder and Board member-Sling Therapeutics; Advisor/Consultant-Radionetics; Advisor/Consultant- Orphagen. C.R.L .: None.
Data Availability
Not applicable.
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