Department of General Surgery, The Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing 210006, People's Republic of China.
Med Oncol. 2012 Sep;29(3):2251-60. doi: 10.1007/s12032-011-0023-9. Epub 2011 Jul 20.
Arsenic trioxide (ATO) has shown anticancer activity against a variety of solid tumor models through induction of apoptosis, promotion of cellular differentiation, and inhibition of cellular invasive ability. The present study investigated the role of ceramide in regulating the invasive activity of hepatoma carcinoma HCCLM3 cells during ATO treatment. We found that ATO treatment inhibited HCCLM3 cell invasion and downregulated matrix metalloproteinase-9 (MMP-9) protein levels in a concentration-dependent manner. ATO also dose dependently induced the generation and accumulation of ceramide in HCCLM3 cells. Blockage of intracellular ceramide production through the inhibition of de novo ceramide synthesis or the hydrolysis of sphingomyelin increased the invasive ability and upregulated MMP-9 protein levels. The findings of this study indicated that ATO induced ceramide production through de novo ceramide synthesis and the hydrolysis of sphingomyelin and suggested that ceramide accumulation in response to ATO stimuli may play an important role in cancer therapy.
三氧化二砷（ATO）通过诱导细胞凋亡、促进细胞分化和抑制细胞侵袭能力，对多种实体瘤模型显示出抗癌活性。本研究探讨了神经酰胺在调节 ATO 处理过程中肝癌细胞 HCCLM3 侵袭活性中的作用。我们发现 ATO 处理以浓度依赖的方式抑制 HCCLM3 细胞侵袭并下调基质金属蛋白酶-9（MMP-9）蛋白水平。ATO 还剂量依赖性地诱导 HCCLM3 细胞中神经酰胺的产生和积累。通过抑制从头合成神经酰胺或水解鞘磷脂来阻断细胞内神经酰胺的产生，增加了侵袭能力并上调了 MMP-9 蛋白水平。本研究的结果表明，ATO 通过从头合成神经酰胺和水解鞘磷脂诱导神经酰胺的产生，并表明对 ATO 刺激的神经酰胺积累可能在癌症治疗中起重要作用。
