Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer

摘要

BACKGROUND Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B(NF-κB)pathway,resulting in the proliferation of tumor cells.Treatment with fluorouracil(5-FU)might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway.AIM To detect whether interleukin(IL)-1 receptor antagonist(IL-1RA)could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells.METHODS Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines.Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6,IL-8,IL-17,IL-21 and TLR4 in colon cancer cell lines.We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1αfeedforward loop,which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth.RESULTS IL-1 receptor antagonist could decrease the expression of IL-1αand IL-1βand downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells.Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line,and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line.CONCLUSION Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs.IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.