Alkaline Ceramidase 2 (ACER2) and Its Product Dihydrosphingosine Mediate the Cytotoxicity of N-(4-Hydroxyphenyl)retinamide in Tumor Cells
Alkaline Ceramidase 2 (ACER2) and Its Product Dihydrosphingosine Mediate the Cytotoxicity of N-(4-Hydroxyphenyl)retinamide in Tumor Cells
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DOI：
10.1074/jbc.m110.105296
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发表时间：
2010-09-17
影响因子：
4.8
通讯作者：
Mao, Cungui
中科院分区：
文献类型：
--
作者：
Mao, Zhehao;Sun, Wei;Mao, Cungui
二氢鞘氨醇（DHS），一种生物活性的鞘脂，产生的增加与合成类维生素A N-（4-羟基苯基）视黄酰胺（4-HPR）在肿瘤细胞中的细胞毒性有关。然而，4-HPR如何增加DHS仍不清楚。在这里，我们证明，4-HPR增加的表达，催化水解的二氢神经酰胺，产生DHS的ACER 2，和ACER 2的上调在介导的4-HPR诱导的生成DHS以及4-HPR在肿瘤细胞中的细胞毒性中起着关键作用。用4-HPR处理通过抑制二氢神经酰胺去饱和酶（DES）活性诱导二氢神经酰胺（DHCs）在肿瘤细胞中的积累，所述DES催化DHCs转化为神经酰胺。用4-HPR处理也通过视黄酸受体非依赖性和半胱天冬酶依赖性方式增加ACER 2表达。过表达ACER 2增强了4-HPR诱导的DHS生成以及4-HPR的细胞毒性，以及4-HPR诱导的肿瘤细胞死亡，而敲低ACER 2则具有相反的效果。沿着用另一种DES抑制剂GT 11处理的ACER 2过表达显著增加细胞DHS，导致肿瘤细胞死亡，而单独的ACER 2过表达或GT 11处理不能做到这一点，这表明ACER 2上调和DES抑制对于介导4-HPR诱导的DHS积累、细胞毒性和肿瘤细胞死亡是必要的和足够的。总之，这些结果表明，上调的ACER 2/DHS途径介导的细胞毒性的4-HPR在肿瘤细胞和上调或激活ACER 2可能会提高抗癌活性的4-HRR和其他DHC诱导剂。
Increased generation of dihydrosphingosine (DHS), a bioactive sphingolipid, has been implicated in the cytotoxicity of the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) in tumor cells. However, how 4-HPR increases DHS remains unclear. Here we demonstrate that 4-HPR increases the expression of ACER2, which catalyzes the hydrolysis of dihydroceramides to generate DHS, and that ACER2 up-regulation plays a key role in mediating the 4-HPR-induced generation of DHS as well as the cytotoxicity of 4-HPR in tumor cells. Treatment with 4-HPR induced the accumulation of dihydroceramides (DHCs) in tumor cells by inhibiting dihydroceramide desaturase (DES) activity, which catalyzes the conversion of DHCs to ceramides. Treatment with 4-HPR also increased ACER2 expression through a retinoic acid receptor-independent and caspase-dependent manner. Overexpression of ACER2 augmented the 4-HPR-induced generation of DHS as well as 4-HPR cytotoxicity, and 4-HPR-induced death in tumor cells, whereas knocking down ACER2 had the opposite effects. ACER2 overexpression, along with treatment with GT11, another DES inhibitor, markedly increased cellular DHS, leading to tumor cell death, whereas ACER2 overexpression or GT11 treatment alone failed to do so, suggesting that both ACER2 up-regulation and DES inhibition are necessary and sufficient to mediate 4-HPR-induced DHS accumulation, cytotoxicity, and death in tumor cells. Taken together, these results suggest that up-regulation of the ACER2/DHS pathway mediates the cytotoxicity of 4-HPR in tumor cells and that up-regulating or activating ACER2 may improve the anti-cancer activity of 4-HRR and other DHC-inducing agents.