Targeted Blocking of Nuclear Import Kills Glioblastoma via Proteotoxic Stress
A recent study published in Oncogene demonstrated that glioblastoma (GBM) cells depleted of the nuclear import receptor KPNB1 exhibits proteotoxic stress and apoptosis. This work was performed by researchers in Dr. XIONG Zhi-Qi’s Lab at the Institute of Neuroscience, Chinese Academy of Sciences. This work has uncovered the molecular mechanism of cell apoptosis upon KPNB1 targeting, pointing to new strategies against GBM.

Malignant glioma is the most common primary malignant brain tumor. WHO grade IV gliomas including GBM have poor prognosis, with 1 year survival rate of 35.7 % and 5 year survival rate of 4.7%. GBM is incurable with current therapies, which urgently requires deeper understanding of its molecular pathology to identify new therapeutic targets and to develop therapeutic strategies.

KPNB1 expression is positively correlated with the malignancy and survival probability of glioma. KPNB1 regulates multiple events of mitosis and mediates nuclear import of proteins with classic nuclear localization sequences, endowing tumor cells with capacities like malignant proliferation, which makes KPNB1 as a potential anticancer target. Inhibition of KPNB1 induces apoptotic cell death in tumor cells and decreases tumor growth, but the underlying molecular mechanism is not fully elucidated.

In this study, researchers found that shRNA- or chemical inhibitor-mediated inhibition of expression or function of KPNB1 in GBM cells suppressed cell growth and triggered apoptosis but did not cause mitotic arrest or abnormality in mitotic exit. KPNB1 inhibition increased expression of pro-apoptotic proteins Puma and Noxa and compromised the function of anti-apoptotic proteins Mcl-1 and Bcl-xL favoring apoptosis. Accordingly, combinatory use of KPNB1 inhibitor with Bcl-xL inhibitors aggravated apoptosis.

Given that KPNB1 mediates nuclear import of many cargos, researchers postulated that KPNB1 inhibition might result in protein mislocalization and protein homeostasis disturbance that would trigger stress response. Further studies showed that KPNB1 inhibition in GBM cells caused cytosolic retention and ubiquitination of its cargo p65, bindings of chaperones and autophagy-associated proteins to p65. It also led to cytosolic aggregation of ubiquitinated proteins, activation of PERK/eIF2α/ATF4 axis of unfolded protein response (UPR) and upregulation of Puma and Noxa. These results support initial postulation. Upon KPNB1 inhibition, cells halted protein synthesis by UPR and degraded proteins by autophagic and proteasomal pathways so as to alleviate protein overload and cytotoxicity. Lysosome and proteasome inhibitors thus potentiated the pro-apoptotic effect of KPNB1 inhibitor by accelerating protein overload

Taken together, this work uncovers the role of KPNB1 in maintaining proteostasis in GBM cells and demonstrates the feasibility of targeting KPNB1 against GBM. The mechanistic results provide opportunities for rational combination of KPNB1 inhibitor and other anticancer drugs to treat GBM.

This work entitled “KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells” was published online in Oncogene on March 9, 2018. This work was carried out by Dr. ZHU Zhi-Chuan and colleagues. This work was supported by CAS Strategic Priority Research Program and grants from National Natural Science Foundation of China and Ministry of Science and Technology of China.

Figure legend: Question (upper left), schematic model (down left) and molecular mechanism (right).