Extracellular chaperonin 10 augments apoptotic cell death induced by 5-fluorouracil in human colon cancer cells

Abstract

Aims and background. The molecular mechanisms involved in resistance to 5-fluorouracil (5-FU) in colon cancer patients remain to be elucidated. The purpose of this study was to identify proteins associated with 5-FU resistance in colon cancer. Methods and study design. Proteins secreted from a 5-FU-resistant human colon cancer cell line (SNU-C4 5-FU 200) were analyzed by two-dimensional gel electrophoresis- based proteomics, and identified using matrix-associated laser desorption/ionization-mass spectroscopy analysis and SWISS-PROT database searches. The expression levels of candidate proteins were determined by Western blotting and cell proliferation was monitored by MTT assay. Results. Chaperonin 10 (cpn10) was secreted at a lower level by 5-FU-resistant cells compared to the non-resistant parent cell line. The proliferation of both the parent and 5-FU-resistant cell lines increased slightly when extracellular cpn10 alone was added. However, in the presence of 5-FU, cpn10 augmented 5-FU-induced apoptotic death in both cell lines. Cpn10 led to activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and a specific ERK 1/2 inhibitor, PD98059, completely inhibited cpn10-stimulated cell proliferation. Conclusions. Our findings indicate that concurrent treatment with cpn10 and 5-FU warrants further investigation in an effort to overcome 5-FU resistance and enhance the efficacy of 5-FU therapy for colon cancer.