Inhibition of the nuclear transporter, Kpnβ1, results in prolonged mitotic arrest and activation of the intrinsic apoptotic pathway in cervical cancer cells

This study shows that inhibition of the nuclear import receptor, karyopherin beta 1 (Kpn beta 1), in cancer cells results in a prolonged mitotic arrest and induction of the intrinsic apoptotic pathway, in a p53-independent manner. Non-cancer cells appear unaffected by Kpn beta 1 inhibition.The karyopherin beta proteins are involved in nuclear-cytoplasmic trafficking and are crucial for protein and RNA subcellular localization. We previously showed that Kpn beta 1, a nuclear importin protein, is overexpressed in cervical cancer and is critical for cervical cancer cell survival and proliferation, whereas non-cancer cells are less dependent on its expression. This study aimed to identify the mechanisms by which inhibition of Kpn beta 1 results in cervical cancer cell death. We show that the inhibition of Kpn beta 1 results in the induction of apoptosis and a prolonged mitotic arrest, accompanied by distinct mitotic defects in cervical cancer cells but not non-cancer cells. In cervical cancer cells, Kpn beta 1 downregulation results in sustained degradation of the antiapoptotic protein, Mcl-1, and elevated Noxa expression, as well as mitochondrial membrane permeabilization resulting in the release of cytochrome C and activation of associated caspases. Although p53 becomes stabilized in Kpn beta 1 knockdown cervical cancer cells, apoptosis occurs in a p53-independent manner. These results demonstrate that blocking Kpn beta 1 has potential as an anticancer therapeutic approach.