The online version of this article (https://doi.org/10.1186/s13046-018-0869-1) contains supplementary material, which is available to authorized users.
Metastasis rather than the primary cancer determines the survival of cancer patients. Activation of Akt plays a critical role in the epithelial-to-mesenchymal transition (EMT), the initial step in lung cancer metastasis. Apigenin (API), a flavonoid with a potent Akt-inhibitory effect, shows oncostatic activities in various cancers. However, the effects of API on metastasis of non-small cell lung cancer (NSCLC) remain unclear.
NSCLC cell lines with different epidermal growth factor receptor (EGFR) statuses and in vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. Western blot and genetic knockdown by shRNA or genetic overexpression by DNA plasmids were performed to explore the underlying mechanisms. The Cancer Genome Atlas (TCGA) database was used to investigate the prognosis of API-targeted genes.
API was demonstrated to inhibit the migration/invasion of NSCLC cells harboring different EGFR statuses via suppressing the Snail/Slug-mediated EMT. Mechanistic investigations showed that CD26/dipeptidyl peptidase IV (DPPIV) was downregulated by API following suppressive interplay of Akt and Snail/Slug signaling to modulate the EMT and the invasive ability of NSCLC cells. CD26 expression was positively correlated with the invasive abilities of NSCLC cells and a worse prognosis of lung cancer patients. Furthermore, we observed that patients with CD26high/Akthigh tumors had the shortest recurrence-free survival times. In vivo, API drastically reduced the growth and metastasis of A549 xenografts through targeting CD26.
CD26 may be a useful biomarker for predicting NSCLC progression. API effectively suppressed lung cancer progression by targeting the CD26-Akt-Snail/Slug signaling pathway.
Additional file 1: Figure S1. Effect of apigenin (API) on colony formation in CL1–5 and H1975 non-small cell lung cancer (NSCLC) cells. Figure S2. Effects of apigenin (API) on changes in different proteases in A549 and H1975 cells following 24-h treatment with API. Figure S3. Knockdown of CD26 suppresses Akt activation and the epithelial-to-mesenchymal transition (EMT) in CL1–5 cells. Figure S4. Apigenin (API) inhibits phosphorylation of the epidermal growth factor receptor (EGFR) in EGFR-mutant HCC827 and H1975 cells. (DOCX 431 kb)13046_2018_869_MOESM1_ESM.docx
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- Downregulating CD26/DPPIV by apigenin modulates the interplay between Akt and Snail/Slug signaling to restrain metastasis of lung cancer with multiple EGFR statuses
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