Tetraploidy constitutes an adaptation to stress and an intermediate step between euploidy and
aneuploidy in
oncogenesis.
Tetraploid cells are particularly resistant against genotoxic stress including
radiotherapy and
chemotherapy. Here, we designed a strategy to preferentially kill
tetraploid tumor cells. Depletion of checkpoint kinase-1 (Chk1) by siRNAs, transfection with dominant-negative Chk1 mutants or pharmacological Chk1 inhibition killed
tetraploid colon cancer cells yet had minor effects on their diploid counterparts. Chk1 inhibition abolished the spindle assembly checkpoint and caused premature and abnormal mitoses that led to p53 activation and cell death at a higher frequency in
tetraploid than in diploid cells. Similarly, abolition of the spindle checkpoint by knockdown of Bub1, BubR1 or Mad2 induced p53-dependent apoptosis of
tetraploid cells. Chk1 inhibition reversed the
cisplatin resistance of
tetraploid cells in vitro and in vivo, in xenografted human
cancers. Chk1 inhibition activated p53-regulated transcripts including Puma/BBC3 in
tetraploid but not in diploid
tumor cells. Altogether, our results demonstrate that, in
tetraploid tumor cells, the inhibition of Chk1 sequentially triggers aberrant mitosis, p53 activation and Puma/BBC3-dependent mitochondrial apoptosis.