CXCL-13 Regulates Resistance to 5-Fluorouracil in Colorectal Cancer

Abstract

Purpose5-Fluorouracil (5-Fu) is used as a conventional chemotherapy drug in chemotherapy for patients with advanced colorectal cancer, but many patients still suffer from treatment failure due to 5-Fu resistance. Emerging observations revealed the important role of chemokine (C-X-C motif) ligand 13 (CXCL-13) in tumor microenvironment and its relationship with prognosis in patients with colorectal cancer. This study is designed to reveal the important role of CXCL-13 in causing colorectal cancer resistance to 5-Fu.Materials and MethodsCXCL-13 levels of patient's serum or cell culture supernatants were measured separately by enzyme-linked immunosorbent assay. In cell assays, cell viability is detected by Cell Counting Kit-8. Therefore, the recombinant human CXCL-13 was used to simulate its high expression in cells while its antibody and siRNA were used to reduce CXCL-13 expression in cells.ResultsIn this study, we demonstrated that CXCL-13 is associated with 5-Fu resistance by culture medium exchange experiments and cytokine arrays of colorectal cancer resistant and nonresistant cells. Clinical studies showed that CXCL-13 is highly expressed in the serum of 5-Fu–resistant patients. High levels of serum CXCL-13 also predict a worse clinical outcome. The addition of recombinant CXCL-13 cytokine resulted in 5-Fu resistance, while its antibody overcame 5-Fu resistance, and knockdown of CXCL-13 expression by siRNA also reduced 5-Fu resistance, which can be saved by added recombination CXCL-13.ConclusionThese results not only identify a CXCL-13 mediated 5-Fu resistance mechanism but also provide a novel target for 5-Fu–resistant colorectal cancer in prevention and treatment strategies.

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment

“…The significance of TME in mediating 5-FU drug resistance has also gained attention in recent years due to its crosstalk influence on tumor cell behavior. For instance, in one study, chemokine C-X-C motif ligand 13 (CXCL-13) is found highly-expressed in the TME of 5-FU-resistant colon cancer cells as well as in sera of 5-FU-resistant patients associated with worse clinical outcome [ 145 ]. Although the mechanism as to how CXCL-13 participates in 5-FU resistance was not stated, it is highly plausible that resistance is achieved through piggybacking the same pathways responsible in promoting tumor growth, migration, and invasion in CXCR5-expressing colon cancer cells; through the activation of PI3K/AKT/mTOR and Wnt/β-catenin signaling pathways [ 112 , 146 , 147 ].…”

“…It has been established that TILs are involved in chemotherapy response as elevated levels of chemokine CXCL-13 is determined in sera of 5-FU-resistant patients [ 145 ]. Knockdown of CXCL-13 resulted in re-sensitization of tumor cells with a significant increase in the number of B-cell infiltrating into the tumor cells.…”

CXCL2-mediated ATR/CHK1 signaling pathway and platinum resistance in epithelial ovarian cancer

“…Ren et al demonstrated CXCR3-mediated AMPK signaling pathway contributed to metabolic alteration during the chemoresistance to agent-sorafenib in hepatocellular carcinoma [ 18 ]. Zhang et al identified CXCL13 was involved in 5-Fu resistance in colorectal cancer [ 19 ]. These studies suggested that chemokines and their receptors might be potential novel therapeutic targets of cancer chemoresistance.…”

CXCL2-mediated ATR/CHK1 Signaling Pathway and Platinum Resistance in Epithelial Ovarian Cancer

“…Zhang Guolin et al identi ed CXCL13 was involved in 5-Fu resistance in colorectal cancer [20]. These studies suggested that chemokines and their receptors might be potential novel therapeutic targets of cancer chemoresistance.…”