文献类型：期刊文献

英文题名：KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells

作者：Zhu, Zhi-Chuan[1];Liu, Ji-Wei[2];Li, Kui[1];Zheng, Jing[2];Xiong, Zhi-Qi[1,3,4]

机构：[1]Chinese Acad Sci, Inst Neurosci, CAS Ctr Excellence Brain Sci & Intelligence Techn, State Key Lab Neurosci, Shanghai 200031, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China;[3]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[4]ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China

年份：2018

卷号：37

期号：22

起止页码：2936

外文期刊名：ONCOGENE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000433936300003)】；

基金：This work was supported by grants from National Natural Science Foundation of China (31021063, 91332203, and 31490591), Chinese Academy of Sciences (XDB02020007, QYZDJ-SSW-SMC010), and Ministry of Science and Technology (2016YFA0501002).

语种：英文

摘要：The nuclear import receptor karyopherin beta 1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest. KPNB1 inhibition upregulated Puma and Noxa and freed Mcl-1-sequestered Bax and Bak, leading to mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Moreover, combination of Bcl-xL inhibitors and KPNB1 inhibition enhanced apoptosis in glioblastoma cells. KPNB1 inhibition promoted cytosolic retention of its cargo and impaired cellular proteostasis, resulting in elevated polyubiquitination, formation of aggresome-like-induced structure (ALIS), and unfolded protein response (UPR). Ubiquitination elevation and UPR activation in KPNB1-deficient cells were reversed by KPNB1 overexpression or inhibitors of protein synthesis but aggravated by inhibitors of autophagylysosome or proteasome, indicating that rebalance of cytosolic/nuclear protein distribution and alleviation of protein overload favor proteostasis and cell survival. Chronic activation of eIF2 alpha/ATF4 cascade of UPR was responsible for the upregulation of Puma and Noxa, apoptosis and ABT-263 sensitivity. Taken together, our findings demonstrate that KPNB1 is required for proteostasis maintenance and its inhibition induces apoptosis in glioblastoma cells through UPR-mediated deregulation of Bcl-2 family members.