Curcumin inhibits pancreatic cancer cell invasion and EMT by interfering with tumor‑stromal crosstalk under hypoxic conditions via the IL‑6/ERK/NF‑κB axis.

Hypoxic microenvironment and pancreatic stellate cells (PSCs) play important roles in pancreatic cancer progression. PSCs secrete a number of soluble factors, such as interleukin (IL)-6, to facilitate cancer metastasis. Our previous study revealed that curcumin inhibited the invasive ability of pancreatic cancer cells by modulating epithelial-to-mesenchymal transition (EMT)-related factors. However, whether curcumin could suppress tumor-stromal crosstalk in pancreatic cancer and the underlying mechanisms have yet to be fully elucidated. The aim of the present study was to evaluate whether curcumin could affect pancreatic cancer cell invasion and EMT by interfering with tumor-stromal interaction under hypoxic conditions. The PSCs were treated with curcumin under hypoxic conditions. The activation of PSCs was detected by testing the expression of alpha-smooth muscle actin by western blotting and immunofluorescence analysis. The wound healing assay was used to evaluate the migratory potential of PSCs. The secretion and expression of IL-6 by PSCs was detected by ELISA and reverse transcription-quantitative PCR (RT-qPCR) analysis. BxPC-3 and Panc-1 cells were treated with PSC-conditioned media (PSC-CM), IL-6, IL-6-neutralizing antibody or curcumin under conditions of normoxia or hypoxia. Transwell invasion assay was used to examine the invasive potential of pancreatic cancer cells. The activation of phosphorylated (p-) extracellular signal-regulated kinase (ERK) and p-nuclear factor (NF)-kappa B were measured by western blot analysis. The expression of EMT-related genes at the mRNA and protein levels was detected by RT-qPCR and western blot analysis, respectively. The results of the present study demonstrated that curcumin inhibited the activation and migration of PSCs under hypoxic conditions. Curcumin also suppressed the secretion and expression of IL-6 in PSCs. In addition, curcumin and IL-6-neutralizing antibody treatment suppressed PSC-CM-modulated pancreatic cancer invasion, EMT and the changes in the expression of E-cadherin, vimentin and matrix metallopeptidase-9. Furthermore, the increase in the levels of p-ERK and p-NF-kappa B induced by PSC-CM could be counterbalanced by both curcumin and IL-6-neutralizing antibody treatment under hypoxic conditions. Taken together, these data indicate that curcumin plays an important role in suppressing tumor-stromal crosstalk and pancreatic cancer metastasis by inhibiting the IL-6/ERK/NF-kappa B axis. Blocking the IL-6/ERK/NF-kappa B axis by curcumin may be a promising therapeutic strategy for the treatment of pancreatic cancer.