KPNB1-mediated nuclear import is required for motility and inflammatory transcription factor activity in cervical cancer cells

Abstract

Karyopherin β1 is a nuclear import protein involved in the transport of proteins containing a nuclear localisation sequence. Elevated Karyopherin β1 expression has been reported in cancer and transformed cells and is essential for cancer cell proliferation and survival. Transcription factors such as NFĸB and AP-1 contain a nuclear localisation sequence and initiate the expression of multiple factors associated with inflammation and cancer cell biology. Our study investigated the effect of inhibiting nuclear import via Karyopherin β1 on cancer cell motility and inflammatory signaling using siRNA and the novel small molecule, Inhibitor of Nuclear Import-43, INI-43. Inhibition of Karyopherin β1 led to reduced migration and invasion of cervical cancer cells. Karyopherin β1 is essential for the translocation of NFĸB into the nucleus as nuclear import inhibition caused its cytoplasmic retention and decreased transcriptional activity. A similar decrease was seen in AP-1 transcriptional activity upon Karyopherin β1 inhibition. Consequently reduced interleukin-6, interleukin-1 beta, tumour necrosis factor alpha and granulocyte macrophage colony stimulating factor expression, target genes of NFkB and AP-1, was observed. Migration studies inhibiting individual transcription factors suggested that INI-43 may affect a combination of signaling events. Our study provides further evidence that inhibiting KPNB1 has anti-cancer effects and shows promise as a chemotherapeutic target.

Cytoplasmic sequestration of the RhoA effector mDiaphanous1 by Prohibitin2 promotes muscle differentiation

“…mDia1 interacts with proteins involved in nuclear import and protein folding in MB, suggesting novel stage-specific roles for mDia1 in MB. It's interaction with proteins regulating nuclear import such as Kpnb1, Hsp90ab1and Hsp90aa1 (Hasse and Fitze, 2016;Stelma and Leaner, 2017;Zhong et al, 2014) suggests that mDia1 might shuttle between the nucleus and cytoplasm, similar to mDia2 (Miki et al, 2009;Shao et al, 2015). Consistent with its scaffolding properties (Wallar and Alberts, 2003), mDia1 associates with chaperones such as Hsp90b1, Hsp90ab1, Hsp90aa1 (Schopf et al, 2017), suggesting a potential involvement in regulating protein folding.…”

Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines

“…Lastly, IPZ treatment significantly increased PUMA expression at both mRNA and protein levels ( Figure 3C,D), suggesting that IPZ enhances PUMA expression by preventing ∆Np63 nuclear import. Since KPNB1 blockage was reported to block c-JUN nuclear import [29], the localization of c-JUN was also investigated ( Figure S3). Consistent with previous reports [29], the nuclear levels of c-JUN were inhibited by IPZ ( Figure S3).…”

“…Since KPNB1 blockage was reported to block c-JUN nuclear import [29], the localization of c-JUN was also investigated ( Figure S3). Consistent with previous reports [29], the nuclear levels of c-JUN were inhibited by IPZ ( Figure S3). Of utmost importance is the examination of TCGA RNA-seq datasets that further showed that the expression levels of PUMA are inversely related to the levels of p63 and not of the activator protein 1 (AP-1) family, including c-JUN ( Figure 3E,F and Figure S2B,C).…”

Silencing of carbonic anhydrase I enhances the malignant potential of exosomes secreted by prostatic tumour cells

“…The dynamic reorganization of the actin cytoskeleton is a prerequisite for the morphology, migration and invasion of cancer cells. 56,57 All these proteins are known as building blocks for cell formation and survival. 55 Moreover, up-regulation of importin subunit beta-1 promotes tumour cell proliferation and predicts poor prognosis in non-small lung, cervical, glioma and gastric cancer.…”

“…55 Moreover, up-regulation of importin subunit beta-1 promotes tumour cell proliferation and predicts poor prognosis in non-small lung, cervical, glioma and gastric cancer. 56,57 All these proteins are known as building blocks for cell formation and survival.…”