Shikonin Inhibited Migration and Invasion of Human Lung Cancer Cells via Suppression of c‐Met‐Mediated Epithelial‐to‐Mesenchymal Transition

Abstract

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.

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…It is effective in treating different kinds of cancers, including breast, prostate, ovarian and thyroid cancers, Ewing sarcoma, and myelomonocytic lymphoma [595][596][597][598][599][600]. Shikonin exerts anti-cancer effects mainly by inducing apoptosis, necroptosis, autophagy, cell cycle arrest, and by inhibiting cell proliferation, growth and metastasis [593,601,602].…”

“…However, autophagy provides a protective role in shikonin-induced apoptosis in human melanoma A375 cells [608]. In addition, shikonin can suppress metastasis by the inhibition of tyrosine kinase c-Met and integrin (ITG) β1 in human NSCLC A549 cells [602,611].…”

<p>Regulations of miR-183-5p and Snail-Mediated Shikonin-Reduced Epithelial-Mesenchymal Transition in Cervical Cancer Cells</p>

“…[4][5][6][7][8] It was reported that the anti-migration and anti-invasion activities of shikonin was through inhibition of c-Met followed by suppression of epithelial-mesenchymal transition (EMT) in lung cancer cells. 9 Shikonin showed to exert anticancer effects on gallbladder cancer (GBC) cells by inducing apoptosis and regulating the cell cycle arrest via the c-Jun N-terminal kinase (JNK) signaling pathway. 10 Preliminary clinical trials indicated the potential of shikonin for translation into application in clinical oncology.…”

Shikonin suppresses NEAT1 and Akt signaling in treating paclitaxel-resistant non-small cell of lung cancer

“…Shikonin has been shown to suppress tumor growth by modulating multiple signaling pathways including p21, PI3K, ERK, and p53 (Jeung et al 2016), and overcome cancer drug resistance such as gefitinib-resistance by inhibiting TrxR and activating the EGFR proteasomal degradation pathway (Li et al 2017). Shikonin could also enhance the antitumor effect of gefitinib in EGFR wildtype lung cancer via inhibition of PKM2/stat3/cyclinD1 signaling (Tang et al 2018), and inhibit migration and invasion of lung cancer cells via inhibition of c-Met mediated EMT (Hsieh et al 2017). It has been reported that shikonin could overcome cisplatin resistance, afatinib resistance, and tamoxifen resistance in several cancer types (Li et al 2018;Zhang et al 2017a;Wang et al 2018d).…”