Protein farnesylation inhibitors cause donut-shaped cell nuclei attributable to a centrosome separation defect

Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4997-5002. doi: 10.1073/pnas.1019532108. Epub 2011 Mar 7.

Abstract

Despite the success of protein farnesyltransferase inhibitors (FTIs) in the treatment of certain malignancies, their mode of action is incompletely understood. Dissecting the molecular pathways affected by FTIs is important, particularly because this group of drugs is now being tested for the treatment of Hutchinson-Gilford progeria syndrome. In the current study, we show that FTI treatment causes a centrosome separation defect, leading to the formation of donut-shaped nuclei in nontransformed cell lines, tumor cell lines, and tissues of FTI-treated mice. Donut-shaped nuclei arise during chromatin decondensation in late mitosis; subsequently, cells with donut-shaped nuclei exhibit defects in karyokinesis, develop aneuploidy, and are often binucleated. Binucleated cells proliferate slowly. We identified lamin B1 and proteasome-mediated degradation of pericentrin as critical components in FTI-induced "donut formation" and binucleation. Reducing pericentrin expression or ectopic expression of nonfarnesylated lamin B1 was sufficient to elicit donut formation and binucleated cells, whereas blocking proteasomal degradation eliminated FTI-induced donut formation. Our studies have uncovered an important role of FTIs on centrosome separation and define pericentrin as a (indirect) target of FTIs affecting centrosome position and bipolar spindle formation, likely explaining some of the anticancer effects of these drugs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / biosynthesis
  • Antigens / genetics
  • Antineoplastic Agents / pharmacology*
  • Cell Nucleus* / genetics
  • Cell Nucleus* / metabolism
  • Cell Nucleus* / pathology
  • Centrosome* / metabolism
  • Centrosome* / pathology
  • Hep G2 Cells
  • Humans
  • Lamin Type B / biosynthesis
  • Lamin Type B / genetics
  • Mice
  • Mice, Transgenic
  • Mitosis / drug effects*
  • Mitosis / genetics
  • Progeria / genetics
  • Progeria / metabolism
  • Progeria / pathology
  • Protein Prenylation / drug effects*
  • Protein Prenylation / genetics
  • Spindle Apparatus* / genetics
  • Spindle Apparatus* / metabolism
  • Spindle Apparatus* / pathology

Substances

  • Antigens
  • Antineoplastic Agents
  • Lamin Type B
  • lamin B1
  • pericentrin