The
Karyopherin proteins are involved in nucleo-cytoplasmic trafficking and are critical for
protein and
RNA subcellular localization. Recent studies suggest they are important in nuclear envelope component assembly, mitosis and replication. Since these are all critical cellular functions, alterations in the expression of the
Karyopherins may have an impact on the biology of
cancer cells. In this study, we examined the expression of the
Karyopherins, Crm1,
Karyopherin beta1 (Kpnbeta1) and
Karyopherin alpha2 (Kpnalpha2), in cervical tissue and cell lines. The functional significance of these
proteins to
cancer cells was investigated using individual siRNAs to inhibit their expression. Microarrays, quantitative RT-PCR and immunofluorescence revealed significantly higher expression of Crm1, Kpnbeta1 and Kpnalpha2 in
cervical cancer compared to normal tissue. Expression levels were similarly elevated in
cervical cancer cell lines compared to normal cells, and in transformed epithelial and fibroblast cells. Inhibition of Crm1 and Kpnbeta1 in
cancer cells significantly reduced cell proliferation, while Kpnalpha2 inhibition had no effect. Noncancer cells were unaffected by the inhibition of Crm1 and Kpnbeta1. The reduction in proliferation of
cancer cells was associated with an increase in a subG1 population by cell cycle analysis and
Caspase-3/7 assays revealed increased apoptosis. Crm1 and Kpnbeta1
siRNA-induced apoptosis was accompanied by an increase in the levels of
growth inhibitory proteins, p53, p27, p21 and p18. Our results demonstrate that Crm1, Kpnbeta1 and Kpnalpha2 are overexpressed in
cervical cancer and that inhibiting the expression of Crm1 and Kpnbeta1, not Kpnalpha2, induces
cancer cell death, making Crm1 and Kpnbeta1 promising candidates as both
biomarkers and potential anticancer therapeutic targets.