Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Pigment Cell Melanoma Res. 2012 Mar;25(2):259-74. doi: 10.1111/j.1755-148X.2012.00970.x.
Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage-dependent and -independent growth as well as sensitized melanoma cells to apoptosis-inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents.
黑色素瘤对治疗的耐药性迅速发展，导致疾病更加侵袭性。因此，需要有专门针对控制这种疾病发展的蛋白质或途径的药物，这些药物可以根据特定患者肿瘤中失调的基因进行组合。本研究表明，在晚期黑色素瘤中，由于鞘氨醇激酶-1（SPHK1）活性增加而导致的鞘氨醇-1-磷酸（S-1-P）水平升高。使用 siRNA 靶向 SPHK1 可降低锚定依赖性和非依赖性生长，并使黑色素瘤细胞对凋亡诱导剂敏感。药理学 SPHK1 抑制剂 SKI-I 而非 SKI-II 可降低 S-1-P 含量，升高神经酰胺水平，导致 G2-M 阻滞，并诱导黑色素瘤细胞发生凋亡性细胞死亡。使用 siRNA 或称为 SKI-I 的药理学试剂靶向 SPHK1 可降低 pAKT 水平。此外，SKI-I 抑制 CYCLIN D1 蛋白的表达并增加 caspase-3/7 的活性，进而导致 PARP 的降解。在动物中，SKI-I 而非 SKI-II 可使黑色素瘤的生长延缓 25-40%。因此，使用 siRNA 或 SKI-I 靶向 SPHK1 具有治疗黑色素瘤的潜力，无论是单独使用还是与其他靶向药物联合使用。
