Colon cancer chemopreventive drugs modulate integrin-mediated signaling pathways.

Abstract

Epidemiological studies of colorectal cancer incidence suggest that the development of this disease can be modulated by dietary factors. Among the micronutrients showing significant efficacy in tumor prevention are polyphenolic antioxidants found in fruits and vegetables. Epidemiological studies also indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of colorectal cancer. Integrin-mediated cell-matrix contact provides critical signaling that regulates cellular proliferation, migration, and apoptosis. A signaling mediator for this system is focal adhesion kinase (FAK). Thus far, FAK has not been identified as a target for the inhibitory action of any chemopreventive drug in vivo or in vitro. However, the loss of integrin-mediated cell-matrix contact can induce apoptosis (anoikis), and effective chemopreventive agents typically increase the rate of enterocyte apoptosis. Therefore, we asked whether the NSAID, sulindac sulfide, and the phenolic antioxidant, caffeic acid phenethyl ester (CAPE), affected FAK expression or tyrosine phosphorylation in human colon carcinoma cells. We show that subapoptotic doses of both sulindac sulfide and CAPE caused a rearrangement of the actin cytoskeleton and consequently the loss of focal adhesion plaques. These drugs also reduced the tyrosine phosphorylation of FAK and an associated factor, p130Cas. Steady-state levels of these proteins, together with other relevant signaling molecules, remained unchanged after treatments. Finally, we show that both CAPE and sulindac reduced cell invasion, a functional assay for the inhibition of signaling downstream of FAK. These data strongly suggest that chemopreventive drugs can regulate FAK activity. In conclusion, these novel studies add modulation of integrin-mediated signaling to the spectrum of activity of NSAIDs and plant phenolics.

• Authors: M J Weyant, A M Carothers, M E Bertagnolli, M M Bertagnolli
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 3 Pg. 949-56 (Mar 2000) ISSN: 1078-0432 [Print] United States
• PMID: 10741720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Actins
• Antineoplastic Agents
• BCAR1 protein, human
• Caffeic Acids
• Crk-Associated Substrate Protein
• Integrins
• Phosphoproteins
• Proteins
• Retinoblastoma-Like Protein p130
• Sulindac
• sulindac sulfide
• Protein-Tyrosine Kinases
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• PTK2 protein, human
• caffeic acid phenethyl ester
• Phenylethyl Alcohol

Topics

• Actins (drug effects, metabolism)
• Antineoplastic Agents (pharmacology)
• Caffeic Acids (pharmacology)
• Cell Movement (drug effects)
• Colonic Neoplasms (pathology, physiopathology, prevention & control)
• Crk-Associated Substrate Protein
• Focal Adhesion Kinase 1
• Focal Adhesion Protein-Tyrosine Kinases
• Humans
• Integrins (physiology)
• Phenylethyl Alcohol (analogs & derivatives, pharmacology)
• Phosphoproteins (drug effects, metabolism)
• Phosphorylation (drug effects)
• Protein-Tyrosine Kinases (drug effects, metabolism)
• Proteins
• Retinoblastoma-Like Protein p130
• Signal Transduction (drug effects)
• Sulindac (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured