Aneuploidy a new anticancer target?
Aneuploidy, an incorrect chromosome number, is a hallmark of cancer. In this study, we carried out a chemical screen in primary mouse embryonic fibroblasts (MEFs) that harbor three copies of either Chromosome 1, 13, 16 or 19 (trisomic MEFs). The screen identified the energy stress-inducing agent AICAR, the protein folding inhibitor 17-AAG and the autophagy inhibitor chloroquine as preferentially impairing the growth of trisomic MEFs compared to euploid control cells. Our analyses further showed that these compounds induce p53-mediated apoptosis in trisomic MEFs. And also show efficacy in aneuploid human cancer cell lines, particularly when used together. Our results suggest that compounds which are interfering with essential survival pathways in aneuploid cells could serve as a new treatment strategy to antagonize the growth of a broad spectrum of human tumors.
HFSP Long-Term Fellow Yun-Chi Tang and colleagues
Aneuploidy describes an abnormal number of chromosomes that is not a multiple of the haploid complement.Examination of aneuploid budding yeast, mouse and human cells revealed cell proliferation defects. Although aneuploidy adversely affects cell proliferation, this condition is often associated with cancer, a disease with unabated growth. Whether aneuploidy is simply a by-product of cancer or promotes tumor formation remains to be answered, yet more than 90 percent of all solid human tumors carry numerical karyotype abnormalities.
Irrespective of whether and how aneuploidy promotes tumorigenesis, the stresses caused by the aneuploid state could still exist in aneuploid cancer cells, a condition termed “non-oncogene addiction”. We have identified that the AMPK activator AICAR, the Hsp90 inhibitor 17-AAG and autophagy inhibitor chloroquine impair growth in primary mouse embryonic fibroblasts (MEF) trisomic for either Chromosome 1, 13, 16 or 19. We observe a correlation between the degree of sensitivity to these compounds and chromosome size, which suggests that the compounds synergize with the more general effects of aneuploidy, rather than with the effects of gene copy number imbalances of individual genes.Our studies also suggest potential mechanisms whereby the compounds impair growth of aneuploidy cells. AICAR, 17-AAG and chloroquine induce p53-mediated apoptosis in trisomic MEFs. However, simply activating p53 is not sufficient to cause this aneuploidy specific apoptosis. Our studies further suggested that these compounds aggravate the already stressed proteostasis and energy homeostasis in aneuploid cells judged by higher levels of autophagy and active Hsp72. We propose that this increases the cell’s susceptibility to apoptosis.
AICAR and 17-AAG also show efficacy against primary MEFs with mutations in BUBR1 or CDC20, where aneuploidies are spontaneously generated due to increased chromosome mis-segregation. The effects of the compounds are also observed in aneuploid human cancer cell lines. When AICAR and 17-AAG are combined, the two compounds effectively inhibit the proliferation of human colorectal cancer cells that exhibit high grade aneuploidy (chromosome instability lines, CIN) compared to lines that show low grade aneuploidy (microsatellite instability lines, MIN). Our results raise the interesting possibility that the aneuploid state of a cancer cell can be exploited in cancer therapy.
Reference:
Identification of aneuploidy-selective antiproliferation compounds. Tang, Y-C., Williams, B.R., Siegel, J.J., and Amon, A. (2011). Cell. 144(4):499-512.
