Malignant glioma is the most common primary malignant brain tumor. WHO grade IV gliomas including glioblastoma (GBM) have poor prognosis. Though incurable with current therapies, GBM needs deeper understanding of its molecular pathology to identify new therapeutic targets and to develop therapeutic strategies.

As a potential anticancer target, karyopherin β1 (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. Inhibition of KPNB1 induces apoptotic cell death in tumor cells and decreases tumor growth, but the underlying molecular mechanism is not fully elucidated.

In a recent study published in Oncogene, Dr. XIONG Zhiqi’s lab at the Institute of Neuroscience of Chinese Academy of Sciences (CAS) demonstrated that GBM cells depleted of the nuclear import receptor KPNB1 exhibit proteotoxic stress and apoptosis, uncovering the molecular mechanism of cell apoptosis upon KPNB1 targeting, pointing to new strategies against GBM.

The 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.rational combination of KPNB1 inhibitor and other anticancer drugs to treat GBM. 

Given that KPNB1 mediates nuclear import of many cargos, they 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 study uncoversed the role of KPNB1 in maintaining proteostasis in GBM cells and demonstrated the feasibility of targeting KPNB1 against GBM. The mechanistic results provided opportunities for