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

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.

Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells

“…GDF15 neutralization in non-human primates decreased levels of cisplatin-induced weight [27][28][29]. Conversely, 5-FU-resistant CRC cells express lower levels of GDF15 compared to 5-FU-sensitive cells and transient expression of GDF15 restores sensitivity, suggesting that this gene plays an important role in 5-FU-mediated cell death [30]. Therefore, GDF15 likely plays a multiplex role in the response to chemotherapy and careful investigation is needed before combination therapies are considered.…”

Regulation Network of Colorectal-Cancer-Specific Enhancers in the Progression of Colorectal Cancer

“…In addition, M SLN and GDF15 were found to be significantly upregulated (fold change = 12.24 for M SLN and fold change = 14.76 for GDF15 ) in colorectal cancer tissues, as well as to interact with colorectal-cancer-specific enhancers in colorectal cancer cells ( Figure 6 C, D). Mesothelin (MSLN) is reportedly associated with the prognosis of colorectal cancer [ 27 ], and growth differentiation factor 15 (GDF15) is reportedly associated with the recurrence and 5-fluorouracil resistance of colorectal cancer [ 28 , 29 , 30 ]. ChIP and HiChIP data showed that several colorectal-specific enhancers interact with M SLN and GDF15 , and some of these enhancers interact with M SLN or GDF15 through long-range chromatin interactions (>20 kb) ( Figure 6 C,D).…”

The Synergism of Natural Compounds and Conventional Therapeutics against Colorectal Cancer Progression and Metastasis

“…5-FU-resistant colon cancer cells have enhanced EMT and antiapoptotic capacity. Drug-resistant cells generally exhibit accelerated proliferation and distant metastases [59]. The combination of natural compounds with 5-FU treatment can inhibit colon cancer progression and metastases by inhibiting epithelial-stromal transformation and promoting apoptosis.…”