Curcumin inhibits the cancer-associated fibroblast-derived chemoresistance of gastric cancer through the suppression of the JAK/STAT3 signaling pathway

The present study aimed to investigate whether the Janus-activated kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a critical mechanism underlying the cancer-associated fibroblast (CAF)-induced chemoresistance of gastric cancer (GC). In addition, the present study tried to suggest a natural product to compromise the effects of CAF on the chemoresistance of GC. The results of cell proliferation assay revealed that the conditioned medium (CM) collected from CAFs further increased resistance to 5-fluorouracil (5-FU) in GC cell lines. Secretome analysis revealed that the levels of several secreted proteins, including C-C motif chemokine ligand 2, C-X-C motif chemokine ligand 1, interleukin (IL)-6 and IL-8, were increased in the CM from CAFs co-cultured with cancer cells compared to CM from cancer cells. Western blot analysis revealed that CAFs activated the JAK/STAT3 signaling pathway in cancer cells. The experimental models revealed that curcumin abrogated the CAF-mediated activation of the JAK/STAT3 signaling pathway in GC cells. In vivo data revealed the synergistic effects of curcumin with 5-FU treatment in xenograft GC tumors. These data strongly suggest that the suppression of the JAK/STAT3 signaling pathway counteracts the CAF-induced chemoresistance of GC cells. It is suggested that curcumin may be a suitable natural product which may be used to overcome chemoresistance by inhibiting the CAF-induced activation of the JAK/STAT3 signaling pathway in GC.

Automated summary

This study aimed to investigate the role of the JAK/STAT3 signaling pathway in the chemoresistance of gastric cancer induced by cancer-associated fibroblasts (CAF). The results showed that CAFs increased the resistance of gastric cancer cells to chemotherapy, and this was associated with the activation of the JAK/STAT3 pathway. However, the natural product curcumin was found to inhibit the activation of this pathway and sensitize the cancer cells to chemotherapy. These findings suggest that targeting the JAK/STAT3 pathway may be a potential strategy to overcome chemoresistance in gastric cancer, and curcumin could be a promising natural compound for this purpose.