GDF15 Repression Contributes to 5-Fluorouracil Resistance in Human Colon Cancer by Regulating Epithelial-Mesenchymal Transition and Apoptosis

• Published in: BioMed research international 2020, Vol.2020 (2020), p.1-9
• Main Authors: Cao, Bangwei, Ma, Xiao, Li, Xiao, Zheng, Xixi, Ma, Nina, Wang, Bin, Hu, Jiexuan
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Bone growth; Cancer; Cancer therapies; Causes of; Cell adhesion & migration; Cell differentiation; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemotherapy; Colon; Colon cancer; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug therapy; Epithelial cells; Epithelial-Mesenchymal Transition - drug effects; Fluorouracil; Fluorouracil - pharmacology; Genetic aspects; Growth Differentiation Factor 15 - metabolism; Growth Differentiation Factor 15 - pharmacology; Growth factors; Growth inhibition; Health aspects; Humans; Male; Mesenchyme; Metastasis; Mice, Nude; Oncology, Experimental; Patient outcomes; Proteins; Reverse transcription; Software; Statistical analysis; Stem cells; Transforming growth factor-b; Transforming growth factors; Western blotting; Wound healing
• ISSN: 2314-6133; 2314-6141
• DOI: 10.1155/2020/2826010

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.