This study was designed to determine how
aspirin influences the growth kinetics and characteristics of cultured
colorectal cancer cells that harbor a variety of different mutational backgrounds, including PIK3CA- and KRAS-activating mutations, and the presence or absence of
microsatellite instability.
Colorectal cancer cell lines (HCT116, HCT116 + Chr3/5, RKO, SW480, HCT15, CACO2, HT29, and SW48) were treated with pharmacologically relevant doses of
aspirin (0.5-10 mmol/L) and evaluated for proliferation and cell-cycle distribution. These parameters were fitted to a mathematical model to quantify the effects and understand the mechanism(s) by which
aspirin modifies growth in
colorectal cancer cells. We also evaluated the effects of
aspirin on key G0-G1 cell-cycle genes that are regulated by the PI3K-Akt pathway.
Aspirin decelerated growth rates and disrupted cell-cycle dynamics more profoundly in faster growing
colorectal cancer cell lines, which tended to be PIK3CA mutants. Additionally, microarray analysis of 151
colorectal cancer cell lines identified important cell-cycle regulatory genes that are downstream targets of PIK3 and were also dysregulated by
aspirin treatment (
PCNA and RB1). Our study demonstrated what clinical trials have only speculated, that PIK3CA-mutant
colorectal cancers are more sensitive to
aspirin.
Aspirin inhibited cell growth in all
colorectal cancer cell lines regardless of mutational background, but the effects were exacerbated in cells with PIK3CA mutations. Mathematical modeling combined with bench science revealed that cells with PIK3CA-mutations experience significant G0-G1 arrest and explains why patients with PIK3CA mutant
colorectal cancers may benefit from
aspirin use after diagnosis.
Cancer Prev Res; 10(3); 208-18. ©2017 AACR.