Sterol O-Acyl transferase 1 as a prognostic marker of adrenocortical carcinoma

Abstract Background: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved, largely due to the rarity of these tumors. Therefore, the discovery of new prognostic biomarkers that could guide and improve the management of patients with ACC is of enormous interest. Sterol-O-Acyl Transferase 1 (SOAT1) is involved in cholesterol esterification in adrenocortical cells. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC [1]. There are no studies so far addressing the impact of SOAT1 protein expression in ACC prognosis and clinical outcomes. Methods: We evaluated SOAT1 protein expression by immunohistochemistry (ab39327; 1:4000; Abcam, EUA) in a tissue microarray of 107 adrenocortical carcinomas (Weiss score ≥ 3) from adult patients treated in a single tertiary center in Brazil. Immunohistochemistry results were evaluated through a semiquantitative approach by two independent pathologists. We aimed to evaluate the correlation of SOAT1 protein expression with clinical and biochemical parameters, surgical specimen histological characteristics, recurrence free-survival, progression free-survival and overall survival. Results: SOAT1 protein expression was heterogenous in this cohort; 38% of ACCs demonstrated strong SOAT1 protein expression while 62% demonstrated weak or absent SOAT1 protein expression. Strong SOAT1 protein expression correlates with known features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p= 0.007), advanced disease stage [ENSAT 3 and ENSAT 4 (p= 0.009)] and high Ki67 index (0.008). On multivariate analysis, strong SOAT1 protein expression was an independent predictor of lower overall survival (HR 1.71, CI 95% 1.05-2.92; p= 0.04) when considering all cases (n= 107) and of lower progression free survival (HR 3.05, CI 95% 1.05-8.85; p= 0.04) in patients with metastatic disease at diagnosis (n= 22). Conclusions: Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforce the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC. Multicentric prospective studies including a larger number of patients are needed in order to validate and consolidate the results found in this cohort. References: 1. Sbiera S, Leich E et al. Mitotane inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells. Endocrinology. 2015; 156 (11):3895-908.

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Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma

Frontiers in Endocrinology ◽

10.3389/fendo.2019.00487 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Claudia Siebert ◽

Denis Ciato ◽

Masanori Murakami ◽

Ludwig Frei-Stuber ◽

Luis Gustavo Perez-Rivas ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Prognostic Marker ◽

Adrenocortical Carcinoma ◽

Therapeutic Target ◽

Heat Shock Protein 90

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Sterol O-Acyl Transferase 1 as a Prognostic Marker of Adrenocortical Carcinoma

Cancers ◽

10.3390/cancers12010247 ◽

2020 ◽

Vol 12 (1) ◽

pp. 247 ◽

Cited By ~ 1

Author(s):

Amanda Meneses Ferreira Lacombe ◽

Iberê Cauduro Soares ◽

Beatriz Marinho de Paula Mariani ◽

Mirian Yumie Nishi ◽

João Evangelista Bezerra-Neto ◽

...

Keyword(s):

Protein Expression ◽

Adrenocortical Carcinoma ◽

Treatment Strategies ◽

Disease Stage ◽

Adrenal Tumors ◽

Acyl Transferase ◽

Free Survival ◽

Tertiary Center ◽

The Impact ◽

Expression Score

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0–4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26–3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09–4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.

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Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells

Endocrinology ◽

10.1210/en.2015-1367 ◽

2015 ◽

Vol 156 (11) ◽

pp. 3895-3908 ◽

Cited By ~ 92

Author(s):

Silviu Sbiera ◽

Ellen Leich ◽

Gerhard Liebisch ◽

Iuliu Sbiera ◽

Andreas Schirbel ◽

...

Keyword(s):

Mass Spectrometry ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Adrenocortical Carcinoma ◽

Initiation Factor ◽

Acyl Transferase ◽

Hormone Production ◽

Tissue Samples ◽

Dismal Prognosis ◽

Mass Spectrometry Technology

Adrenocortical carcinoma (ACC) is a rare malignancy that harbors a dismal prognosis in advanced stages. Mitotane is approved as an orphan drug for treatment of ACC and counteracts tumor growth and steroid hormone production. Despite serious adverse effects, mitotane has been clinically used for decades. Elucidation of its unknown molecular mechanism of action seems essential to develop better ACC therapies. Here, we set out to identify the molecular target of mitotane and altered downstream mechanisms by combining expression genomics and mass spectrometry technology in the NCI-H295 ACC model cell line. Pathway analyses of expression genomics data demonstrated activation of endoplasmic reticulum (ER) stress and profound alteration of lipid-related genes caused by mitotane treatment. ER stress marker CHOP was strongly induced and the two upstream ER stress signalling events XBP1-mRNA splicing and eukaryotic initiation factor 2 A (eIF2α) phosphorylation were activated by mitotane in NCI-H295 cells but to a much lesser extent in four nonsteroidogenic cell lines. Lipid mass spectrometry revealed mitotane-induced increase of free cholesterol, oxysterols, and fatty acids specifically in NCI-H295 cells as cause of ER stress. We demonstrate that mitotane is an inhibitor of sterol-O-acyl-transferase 1 (SOAT1) leading to accumulation of these toxic lipids. In ACC tissue samples we show variable SOAT1 expression correlating with the response to mitotane treatment. In conclusion, mitotane confers adrenal-specific cytotoxicity and down-regulates steroidogenesis by inhibition of SOAT1 leading to lipid-induced ER stress. Targeting of cancer-specific lipid metabolism opens new avenues for treatment of ACC and potentially other types of cancer.

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