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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.

journal_name

J Cell Biochem

journal_title

Journal of cellular biochemistry

authors

Hsieh YS,Liao CH,Chen WS,Pai JT,Weng MS

doi

10.1002/jcb.26128

subject

Has Abstract

pub_date

2017-12-01 00:00:00

pages

4639-4651

issue

eissn

0730-2312

issn

1097-4644

journal_volume

118

pub_type

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