Aspirin promotes apoptosis in a murine model of colorectal cancer by mechanisms involving downregulation of IL-6-STAT3 signaling pathway.
OBJECTIVE
Aspirin is associated with a reduced risk of colorectal cancer (CRC), and it showed inhibited effects on interleukin 6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway which is thought to play an important role in intestinal inflammation and the tumorigenesis of CRC.


METHODS
Mouse model for inflammation-related CRC was induced by a combined treatment with azoxymethane (AOM) and dextran sodium sulfate (DSS) in BALB/c mice. Effects of aspirin on tumor number and size and apoptosis of CRC cells were investigated. Key molecules of IL-6-STAT3 pathway, such as IL-6, sIL-6R, phosphorylated STAT3, and their downstream anti-apoptotic genes Bcl-2 and Bcl-xl, were assessed by ELISA and Western blot.


RESULTS
Treatment with aspirin significantly promoted CRC cell apoptosis in AOM/DSS-induced CRC mice in vivo. The expression level of IL-6, which is an upstream molecule of STAT3 and capable of activating STAT3, was reduced in aspirin-treated mice. Furthermore, the phosphorylated form of STAT3 and the levels of STAT3's target gene products such as Bcl-xl and Bcl-2, which are essential for cell growth and survival, were also decreased in aspirin-treated mice.


CONCLUSIONS
Our data suggested that the protective mechanisms of aspirin in CRC may be associated with its effects on induction of CRC cell apoptosis and suppression of IL-6-STAT3 signaling pathway, which implied that aspirin has a potential therapeutic activity in CRC.
Tian
Yun
Y
Cancer Research Institute, the First Affiliated Hospital, China Medical University, Shenyang 110001, China.
Ye
Ying
Y
Gao
Wei
W
Chen
Hong
H
Song
Ting
T
Wang
Daqing
D
Mao
Xiaoyun
X
Ren
Changshan
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051020:bcl-X Protein; D001241:Aspirin