Du Zhen-Xian, Meng Xin, Zhang Hai-Yan, Guan Yifu, Wang Hua-Qin
Department of Endocrinology and Metabolism, The 1st Affiliated Hospital, China Medical University, Shenyang 110001, China.
Biochem Biophys Res Commun. 2008 May 9;369(3):894-8. doi: 10.1016/j.bbrc.2008.02.112. Epub 2008 Mar 4.
Proteasome inhibitors are emerging as effective drugs for the treatment of relapsed/refractory multiple myeloma and possibly some solid tumors. Bcl-2-associated athanogene 3 (BAG3) is a survival protein that has been shown to be stimulated during cell response to stressful conditions, such as exposure to high temperature, heavy metals. We have recently demonstrated that BAG3 is also induced by proteasome inhibitors at the transcriptional level and the induction of BAG3 by proteasome inhibition is antiapoptotic. Here, we demonstrated that although proteasome inhibitors triggered similar upregulation of BAG3 transcript in sensitive and insensitive thyroid cancer cells, persistent increase of BAG3 protein was detected in insensitive cells, whereas less increase or even decrease was observed in sensitive cells. Notably, decrease of BAG3 protein was associated with the appearance of a BAG3 fragment of approximately 40kDa, which appeared to be caspase-dependent. Therefore, caspase-dependent cleavage of BAG3 might facilitate apoptosis in sensitive cells.
蛋白酶体抑制剂正逐渐成为治疗复发/难治性多发性骨髓瘤以及可能的某些实体瘤的有效药物。Bcl-2相关抗凋亡基因3（BAG3）是一种生存蛋白，已证实在细胞对压力条件（如暴露于高温、重金属）的反应过程中它会被激活。我们最近证明，蛋白酶体抑制剂在转录水平上也能诱导BAG3，并且蛋白酶体抑制对BAG3的诱导具有抗凋亡作用。在此，我们证明，尽管蛋白酶体抑制剂在敏感和不敏感的甲状腺癌细胞中引发了相似的BAG3转录上调，但在不敏感细胞中检测到BAG3蛋白持续增加，而在敏感细胞中观察到的增加较少甚至减少。值得注意的是，BAG3蛋白的减少与一个约40kDa的BAG3片段的出现有关，该片段似乎依赖于半胱天冬酶。因此，BAG3的半胱天冬酶依赖性切割可能促进敏感细胞的凋亡。
