title: Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression.
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, knockdown 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.
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yunze
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Baijun
authors.initials: B
authors.lastname: Dong
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Kong
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Department of Urology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000473:pathology*; D000311:Adrenal Glands / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018450:Disease Progression; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D008939:Mitotane / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C466999:SPHKAP protein, human; D008939:Mitotane; D000068876:Fingolimod Hydrochloride
keywords: FTY720; adrenocortical carcinoma; prognosis; progression; sphingosine kinase 1