p14ARF re-expression induces apoptosis in aneuploid HCT116 cells

Abstract

Weakening the Spindle Assembly Checkpoint by reduced expression of its components such as MAD2, BubR1 and MPS1 induces chromosome instability and aneuploidy both hallmarks of cancer cells. p14ARF that is found frequently altered in human cancers, is overexpressed in response to oncogenic stimuli to stabilize p53 halting cell progression. Previously, we determined that lack or reduced expression of p14ARF is involved in the maintenance of aneuploid cells suggesting that it could be part of a pathway controlling proliferation of aneuploidy cells. To investigate further this aspect of p14ARF function it was ectopically expressed in HCT116 cells, a stable near diploid cell line, after MAD2 depletion used as a trigger for aneuploidy. We observed reduction of aneuploid cell numbers as well as decrease of spindle alterations and mitotic abnormalities in these cells in comparison to MAD2 post- transcriptionally silenced cells. In addition p14ARF ectopic expression in MAD2 depleted HCT116 cells induced apoptosis accompanied by increase of p53 and p21WAF1 protein levels. Altogether these results suggest that p14ARF could prevent proliferation of aneuploid tumor cells.