JCEM：Beclin1具有独立于自噬的抗癌效应

泛素–蛋白酶体系统和自噬是细胞内蛋白质降解的两条主要的途径。新兴的证据显示蛋白酶体抑制剂通过阻断泛素–蛋白酶体系统激活自噬。为了确定自噬必需基因Beclin1在蛋白酶体抑制剂介导的甲状腺癌细胞细胞毒性中的作用，来自中国医科大学第一附属医院老年科的张海燕教授及其团队进行了一项研究，该研究发现甲状腺癌细胞暴露于蛋白酶体抑制剂之上时，Beclin1具有独立于自噬的抗癌作用。该研究结果发表在2013年2月的美国《临床内分泌代谢杂志》（The journal of clinical endocrinology & metabolism）上。

该研究中，通过荧光显微镜下acidic–trophic染色和EGF–LC3分布，以及蛋白印迹LC3–Ⅱ转化测量自噬。为了确定Beclin1的作用，细胞被Beclin1质粒或者靶向Beclin1的shRNA转染。分别使用MTT分析和流式细胞仪测量细胞活力和凋亡细胞。

该研究结果表明，蛋白酶体抑制剂减少Beclin1的表达。另外，通过P13K抑制剂3–MA或渥曼青霉素治疗，和降低Beclin1的表达一样，不能影响蛋白酶体抑制剂介导的自噬反应。Beclin1的过度表达加强蛋白酶体抑制剂介导抑制survivin的甲状腺癌细胞细胞毒性。

该研究发现，蛋白酶体抑制剂引起甲状腺癌细胞通过一种独立于Beclin1方式的独立于Beclin1的自噬应答。在甲状腺癌细胞暴露于蛋白酶体抑制剂之上时，Beclin1具有独立于自噬的抗癌作用。

与Beclin1相关的拓展阅读：

• 施一公教授解析Beclin1蛋白新作用
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Beclin 1 enhances proteasome inhibition-mediated cytotoxicity of thyroid cancer cells in macroautophagy-independent manner.
CONTEXT
The ubiquitin-proteasome system and macroautophagy are two major pathways for intracellular protein degradation. Emerging lines of evidence have shown that blockade of ubiquitin-proteasome system by proteasome inhibitors activates macroautophagy.
OBJECTIVE
The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors.
DESIGN
Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy, as well as LC3-II transition using Western blot. To ascertain the effect of Beclin 1, cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1. Cell viability and apoptotic cells were measured using MTT assay and flow cytometry, respectively.
RESULTS
Proteasome inhibitors decreased Beclin 1 expression. In addition, treatment with PI3K inhibitors 3-MA or wortmannin, as well as knockdown of Beclin 1 expression, was unable to affect autophagic responses mediated by proteasome inhibitors. Overexpression of Beclin 1 enhanced proteasome inhibitor-mediated cytotoxicity of thyroid cancer cells via suppression of survivin.
CONCLUSIONS
Proteasome inhibitors cause Beclin 1-independent macroautophagic responses of thyroid cancer cells in a Beclin 1-independent manner. Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors.