Aspirin-Induced Chemoprevention and Response Kinetics Are Enhanced by PIK3CA Mutations in Colorectal Cancer Cells.
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, includingPIK3CA- andKRAS-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-G1cell-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 bePIK3CAmutants. 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 (PCNAandRB1). Our study demonstrated what clinical trials have only speculated, thatPIK3CA-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 withPIK3CAmutations. Mathematical modeling combined with bench science revealed that cells withPIK3CA-mutations experience significant G0-G1arrest and explains why patients withPIK3CAmutant colorectal cancers may benefit from aspirin use after diagnosis.Cancer Prev Res; 10(3); 208-18. ©2017 AACR.
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Timothy J
TJ
Zumwalt
Department of Mathematics and Department of Ecology and Evolutionary Biology, University of California, Irvine, California.
Dominik
D
Wodarz
Department of Mathematics and Department of Ecology and Evolutionary Biology, University of California, Irvine, California.
Natalia L
NL
Komarova
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
Shusuke
S
Toden
Baylor Institute for Immunology Research, Baylor Scott and White Research Institute, Baylor University Medical Center, Dallas, Texas.
Jacob
J
Turner
Baylor Institute for Immunology Research, Baylor Scott and White Research Institute, Baylor University Medical Center, Dallas, Texas.
Jacob
J
Cardenas
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
John
J
Burn
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.
Andrew T
AT
Chan
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
C Richard
CR
Boland
Center for Gastrointestinal Research; Center for Translational Genomics and Oncology, Baylor Scott and White Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas. ajayg@baylorhealth.edu.
Ajay
A
Goel
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000517:prevention & control; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008962:Models, Theoretical; D009154:Mutation; D023041:Xenograft Model Antitumor Assays
D052246:Cyclooxygenase 2 Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D001241:Aspirin