Eritoran Suppresses Colon Cancer by Altering a Functional Balance in Toll-like Receptors That Bind Lipopolysaccharide.
Colorectal carcinogenesis is affected by overexpression of the lipopolysaccharide (LPS) receptors CD14 and TLR4, which antagonize each other by affecting epithelial cell proliferation and apoptosis. Eritoran is an investigational drug for sepsis treatment that resembles the lipid A moiety of LPS and therefore acts as a TLR4 inhibitor. In the present study, we explored the potential therapeutic uses and mechanisms of action of eritoran in reducing colon cancer progression. Eritoran administration via intracolonic, intragastric, or intravenous routes significantly reduced tumor burden in a chemically induced mouse model of colorectal carcinoma. Decreased proliferation and increased apoptosis were observed in mouse tumor cells after eritoran treatment. In vitro cultures of mouse primary tumor spheroids and human cancer cell lines displayed increased cell proliferation and cell-cycle progression following LPS challenge. This effect was inhibited by eritoran and by silencing CD14 or TLR4. In contrast, apoptosis induced by eritoran was eliminated by silencing CD14 or protein kinase Cζ (PKCζ) but not TLR4. Lastly, LPS and eritoran caused hyperphosphorylation of PKCζ in a CD14-dependent and TLR4-independent manner. Blocking PKCζ activation by a Src kinase inhibitor and a PKCζ-pseudosubstrate prevented eritoran-induced apoptosis. In summary, our work offers a preclinical proof of concept for the exploration of eritoran as a clinical treatment, with a mechanistic rationale to reposition this drug to improve the management of colorectal cancer. Cancer Res; 76(16); 4684-95. ©2016 AACR.
Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
Wei-Ting
WT
Kuo
Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Tsung-Chun
TC
Lee
Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan. lchyu@ntu.edu.tw.
Linda Chia-Hui
LC
Yu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004187:Disaccharides / Q000494:pharmacology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D013403:Sugar Phosphates / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D000970:Antineoplastic Agents; D004187:Disaccharides; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D013403:Sugar Phosphates; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C512420:eritoran