Epithelial-to-mesenchymal transition (EMT) is a major process to regulate cell migration and invasion. Inhibition of
epidermal growth factor receptor (EGFR)-mediated EMT by
tyrosine kinase inhibitors (TKIs) is a strategy to prevent
lung cancer invasion. However, drug resistance is emerged and accelerated invasion through other signaling bypassing EGFR after TKIs
therapy. c-Met signaling pathway is highly activated in EGFR-mutated
lung cancer cells. Targeting c-Met signaling pathway may be a strategy to suppress EGFR-independent migration and invasion for
lung cancer therapy. Therefore, we examined the anti-migration and anti-invasion abilities of
shikonin, an active compound from Lithospermum erythrorhizon, in highly and
ligand-induced c-Met activation
lung cancer cells. Our results revealed that cell viability and cell cycle progression did not change under 1 μM of shikoinin treatment in highly c-Met expressive HCC827
lung cancer cells. Endogenous c-Met activation was dose-dependently inhibited and the migration and invasion activity of HCC827 cells were suppressed by
shikonin treatment. Induction of
E-cadherin expression and inhibition of
vimentin, slug, and snail expression by
shikonin was through c-Met-mediated PI3K/Akt and ERK signaling suppression. Furthermore,
hepatocyte growth factor (HGF)-induced migration, invasion and EMT marker change were reversed by
shikonin in low c-Met expressive A549
lung cancer cells. Inhibition of HGF-induced c-Met, PI3K/Akt and
MEK/ERK activation were observed in
shikonin-treated cells. Co-treatment of PI3K/Akt inhibitor or ERK inhibitor with
shikonin enhanced
shikonin-reversed HGF-regulated EMT marker expression. Taken together, the results suggested that the anti-migration and anti-invasion activities of
shikonin was through c-Met inhibition and following by EMT suppression in
lung cancer. J. Cell. Biochem. 118: 4639-4651, 2017. © 2017 Wiley Periodicals, Inc.