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

Carcinogenesis. 2014 May;35(5):1121-31. doi: 10.1093/carcin/bgt491. Epub 2014 Jan 7.

Abstract

The karyopherin β proteins are involved in nuclear-cytoplasmic trafficking and are crucial for protein and RNA subcellular localization. We previously showed that Kpnβ1, 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 Kpnβ1 results in cervical cancer cell death. We show that the inhibition of Kpnβ1 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, Kpnβ1 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 Kpnβ1 knockdown cervical cancer cells, apoptosis occurs in a p53-independent manner. These results demonstrate that blocking Kpnβ1 has potential as an anticancer therapeutic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Cell Cycle Checkpoints / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Membrane Potential, Mitochondrial / genetics
  • Mitosis / genetics*
  • Models, Biological
  • RNA Interference
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / metabolism*
  • beta Karyopherins / genetics*
  • beta Karyopherins / metabolism

Substances

  • KPNB1 protein, human
  • Tumor Suppressor Protein p53
  • beta Karyopherins