Abstract
Chemotherapy based on 5-fluorouracil (5-FU) is the standard approach for colon cancer treatment, and resistance to 5-FU is a significant obstacle in the clinical treatment of colon cancer. However, the mechanisms underlying 5-FU resistance in colon cancer cells remain largely unknown. This study aimed at determining whether 5-FU-resistant colon cancer cells undergo epithelial-mesenchymal transition (EMT) and apoptosis and the role of GDF15—a member of the transforming growth factor β/bone morphogenetic protein super family and a protein known to be involved in cancer progression—in the regulation of EMT and apoptosis of these cells, along with the underlying mechanisms. In vitro apoptosis detection assay, growth inhibition assay, transwell, and wound healing experiments revealed that 5-FU-resistant colon cancer cells possessed enhanced EMT and antiapoptotic ability. These cells also showed a stronger tendency to proliferate and metastasize in vivo. Quantitative reverse transcription-PCR and western blotting revealed that 5-FU-resistant colon cancer cells expressed lower levels of growth differentiation factor 15 (GDF15) than did 5-FU-sensitive colon cancer cells. Moreover, the transient GDF15 overexpression resensitized 5-FU-resistant colon cells to 5-FU. Collectively, these findings indicate the mechanism underlying the 5-FU resistance of colon cancer cells and provide new therapeutic targets for improving the prognosis of colon cancer patients.
Highlights
Resistance to 5-fluorouracil (5-FU) is the primary reason for the failure of traditional chemotherapy for colon cancer [1]
Evidence indicates that epithelialmesenchymal transition (EMT) and apoptosis are involved in tumor progression [2, 3] and that drug-resistant cells often show accelerated proliferation and distant metastasis [4, 5]
Our previous results showed that growth differentiation factor 15 (GDF15) is downregulated in HCT-15/FU drugresistant colon cancer cells compared with drug-sensitive colon cells; these cells showed accelerated proliferation and angiogenesis in vitro and in vivo
Summary
Resistance to 5-fluorouracil (5-FU) is the primary reason for the failure of traditional chemotherapy for colon cancer [1]. Evidence indicates that epithelialmesenchymal transition (EMT) and apoptosis are involved in tumor progression [2, 3] and that drug-resistant cells often show accelerated proliferation and distant metastasis [4, 5]. These findings suggest that both EMT and apoptosis are possibly involved in the development of chemotherapy resistance. Our previous results showed that growth differentiation factor 15 (GDF15) is downregulated in HCT-15/FU drugresistant colon cancer cells compared with drug-sensitive colon cells; these cells showed accelerated proliferation and angiogenesis in vitro and in vivo.
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