Study on CEACAM1 Mediated Cell Death and Antitumor Effects of Metformin in 5-Fluorouracil Resistant Gastrointestinal Cancer Cells

Abstract

Gastrointestinal (GI) cancer has high incidence and death rate in Korea. Thus to understand about tumorigenesis mechanisms and develop the new therapeutic strategies of GI cancer are important for reducing cancer risk. Conventional therapeutic strategies of GI cancers are surgery with chemotherapy, and chemo-radiotherapy. 5-fluorouracil (5-Fu), oxaliplatin, and irinotecan are most widely used for GI cancer. The combination of 5-Fu with oxaliplatin or irinotecan has improved response rate about up to 40-50% for GI cancer patients. However, still the metastasis and recurrence that related with 5-Fu resistance are occurred, it might be needed of basic research about resistance mechanisms and new strategies for improve of therapeutic effects. In this paper, sensitivity to 5-Fu and gene expression pattern as treated with 5-Fu in parental cancer cell lines, SNU-638, SNU-C5, and their 5-Fu resistant cancer cell lines were investigated. Based on this study, the purpose of paper is suggestion of adjuvant 5-Fu to recover the resistance. Because of Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1), known as tumor suppressor gene, expression level was changed as treated with 5-Fu dose-, and time dependent manner in parental cell lines, I was supposed to that CEACAM1 might be correlated with 5-Fu sensitivity. However, oxaliplatin, irinotecan, and radiation affected to CEACAM1 expression level only in parental cancer cell lines. Through this, I suggested that increased CEACAM1 was one of the phenotypes of cell death regulated by chemotherapeutic agents. As a results, I suggested that CEACAM1 could be used as an indicator of chemotherapeutic agents mediated cell death. Metformin, one of the type II diabetics therapeutic agent that was recently reported about anticancer effect. It was also induce CEACAM1 expression level in GI cancer cell lines. Beside of this, metformin has synergistic effect with 5-Fu especially in 5-Fu resistant cancer cell line. In addition, metformin inhibits cell proliferation, increase cell death and cell cycle arrest, and downregulation of cancer stem cell marker genes. These effects of metformin were concomitant of inhibition of DNA replication machinery and mitotic cell cycle genes. According to series of results, I proposed that use of metformin as adjuvant of 5-Fu that might be reduction of 5-Fu resistance, with less clinical severe adverse effects.