Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination.
Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination.
复制标题
SphK2 的过度表达通过 K48/K63 连接的多聚泛素化快速降解细胞质 RXRα 有助于结肠癌的 ATRA 耐药性
DOI：
10.18632/oncotarget.17174
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发表时间：
2017-06-13
期刊：
影响因子：
--
通讯作者：
Qu XJ
中科院分区：
文献类型：
--
作者：
Shi WN;Cui SX;Song ZY;Wang SQ;Sun SY;Yu XF;Li Y;Zhang YH;Gao ZH;Qu XJ
人们对限制类视黄醇治疗癌症疗效的耐药机制知之甚少。鞘氨醇激酶2（SphK2）是一种高度保守的酶，主要位于细胞核和内质网中。与经过充分研究的位于细胞质中的鞘氨醇激酶 1 (SphK1) 不同，人们对 SphK2 的功能知之甚少。在这里，我们表明，SphK2 过表达通过基于赖氨酸 48 (K48) 和赖氨酸 63 (K63) 的多聚泛素化快速降解细胞质视黄酸 X 受体 α (RXRα)，从而导致结肠癌对全反式视黄酸 (ATRA) 治疗产生耐药性。通过体外和体内试验测定，转染 SphK2 的人结肠腺癌 HCT-116 细胞（HCT-116Sphk2 细胞）表现出对 ATRA 治疗的耐药性。 Sphk2 过表达增加了 ATRA 诱导的核 RXRα 向细胞质的输出，然后通过多聚泛素化途径快速降解 RXRα。我们进一步表明，Sphk2 通过（1）K48 连接的蛋白酶体降解和（2）K63 连接的泛素依赖性自噬降解的信号机制激活泛素-蛋白酶体系统。这些结果为 Sphk2 的生物学功能以及 Sphk2 介导的类维生素A治疗耐药性的分子机制提供了新的见解。
The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116Sphk2 cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRα export to cytoplasm and then rapidly degrades RXRα through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy.
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