Abstract
Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, konckdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC.
Highlights
Adrenocortical carcinoma (ACC) is a rare but highly aggressive endocrine malignancy with a 5-year overall survival of around 40% [1,2]
Our results showed that Sphingosine kinase 1 (SphK1) was significantly upregulated at both mRNA and protein levels in ACC samples when compared with adrenocortical adenomas (ACAs) samples (P < 0.001; Figure 1A and 1B)
The SphK1 protein level was upregulated in ACC group compared with the ACA tissues, suggesting a novel signaling pathway that contributes to ACC pathogenesis and aggressive biology
Summary
Adrenocortical carcinoma (ACC) is a rare but highly aggressive endocrine malignancy with a 5-year overall survival of around 40% [1,2]. Therapeutic options for these patients are scarce, radical surgery resection remains the only potentially curative option for ACC until recently; patients often present with advanced localized invasion or initially distant metastases, limiting the opportunity for surgical resection. Despite the combination of cytotoxic drug and mitotane, the overall prognosis is still very poor in cases of advanced ACC [3]. Interference with SphK1 activity by dominant-negative mutants or competitive inhibitors, as well as inhibition of S1P by mAbs or S1P receptors antagonists, could significantly reduce cell proliferation, angiogenesis, and invasion, and increased apoptosis in some cancer cell lines [7,8]
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