KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells

doi:10.1038/s41388-018-0180-9

	KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells
	Zhu, Zhi-Chuan 1; Liu, Ji-Wei 2; Li, Kui 1; Zheng, Jing 2; Xiong, Zhi-Qi1,3,4
	2018-05
发表期刊	ONCOGENE
ISSN	0950-9232
卷号	37 期号:22 页码:2936-2952
发表状态	已发表
DOI	10.1038/s41388-018-0180-9
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.
收录类别	SCI ; SCIE
语种	英语
资助项目	Ministry of Science and Technology[2016YFA0501002]
WOS研究方向	Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS类目	Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity
WOS记录号	WOS:000433936300003
出版者	NATURE PUBLISHING GROUP
WOS关键词	IMPORTIN-BETA ; NUCLEAR IMPORT ; MYELOMA CELLS ; RECEPTOR ; TRANSPORT ; DEATH ; PROLIFERATION ; KPN-BETA-1 ; PHOSPHORYLATION ; INDUCTION
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/23059
专题	生命科学与技术学院_特聘教授组_熊志奇组
通讯作者	Xiong, Zhi-Qi
作者单位	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
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Zhu, Zhi-Chuan,Liu, Ji-Wei,Li, Kui,et al. KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells[J]. ONCOGENE,2018,37(22):2936-2952.
APA	Zhu, Zhi-Chuan,Liu, Ji-Wei,Li, Kui,Zheng, Jing,&Xiong, Zhi-Qi.(2018).KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells.ONCOGENE,37(22),2936-2952.
MLA	Zhu, Zhi-Chuan,et al."KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells".ONCOGENE 37.22(2018):2936-2952.