The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo.
The Sphingosine Kinase 2 Inhibitor ABC294640 Reduces the Growth of Prostate Cancer Cells and Results in Accumulation of Dihydroceramides In Vitro and In Vivo.
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DOI：
10.1158/1535-7163.mct-15-0279
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发表时间：
2015-12
影响因子：
5.7
通讯作者：
Voelkel-Johnson C
中科院分区：
文献类型：
--
作者：
Venant H;Rahmaniyan M;Jones EE;Lu P;Lilly MB;Garrett-Mayer E;Drake RR;Kraveka JM;Smith CD;Voelkel-Johnson C
尽管最近在开发抗去势前列腺癌的新疗法方面取得了进展，但这种疾病的晚期形式仍然是一个主要的治疗挑战。异常的鞘氨醇信号通过鞘氨醇激酶及其产物鞘氨醇-1-磷酸可以促进增殖、耐药、血管生成和炎症。鞘氨醇激酶2抑制剂ABC294640正在接受癌症患者的临床测试，在这项研究中，我们研究了这种一流的抑制剂在抗去势前列腺癌中的作用。在体外，ABC294640降低了前列腺癌细胞的活力以及c-Myc和雄激素受体的表达，而溶酶体酸化增加了。ABC294640还诱导二氢神经酰胺增加3倍以上，这与二氢神经酰胺脱饱和酶(DEGS)活性的抑制呈负相关。鞘氨醇激酶2的表达对于ABC294640介导的二氢神经酰胺的增加是必不可少的。在体内，通过MALDI成像质谱学显示，ABC294640降低了同基因宿主中TRAMP-C2异种移植瘤的生长速度，并增加了肿瘤内的二氢神经酰胺。ABC294640处理组小鼠的血浆中C16-和C24：1-神经酰胺(但不含二氢C16-神经酰胺)水平显著高于赋形剂处理组小鼠。综上所述，我们的结果提示ABC294640可能通过同时抑制鞘氨醇激酶2和二氢神经酰胺脱饱和酶来降低去势抵抗前列腺癌细胞的增殖能力，这为进一步探索这种小分子抑制剂治疗晚期疾病提供了基础。
Despite recent advances in the development of novel therapies against castration resistant prostate cancer, the advanced form of the disease remains a major treatment challenge. Aberrant sphingolipid signaling through sphingosine kinases and their product sphingosine-1-phosphate can promote proliferation, drug resistance, angiogenesis and inflammation. The sphingosine kinase 2 inhibitor ABC294640 is undergoing clinical testing in cancer patients, and in this study we investigated the effects this first-in-class inhibitor in castration resistant prostate cancer. In vitro, ABC294640 decreased prostate cancer cell viability as well as the expression of c-Myc and the androgen receptor while lysosomal acidification increased. ABC294640 also induced a greater than 3-fold increase in dihydroceramides that inversely correlated with inhibition of dihydroceramide desaturase (DEGS) activity. Expression of sphingosine kinase 2 was dispensable for the ABC294640-mediated increase in dihydroceramides. In vivo, ABC294640 diminished the growth rate of TRAMP-C2 xenografts in syngeneic hosts and elevated dihydroceramides within tumors as visualized by MALDI imaging mass spectroscopy. The plasma of ABC294640 treated mice contained significantly higher levels of C16- and C24:1-ceramides (but not dihydro-C16-ceramide) compared to vehicle treated mice. In summary, our results suggest that ABC294640 may reduce the proliferative capacity of castration resistant prostate cancer cells through both, inhibition of sphingosine kinase 2 and dihydroceramide desaturase, which provides a foundation for future exploration of this small molecule inhibitor for the treatment of advanced disease.