Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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.
| Original language | English |
|---|---|
| Article number | 199 |
| Journal | Journal of Experimental and Clinical Cancer Research |
| Volume | 37 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Aug 22 2018 |
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Keywords
- Akt
- Apigenin
- CD26/dipeptidyl peptidase IV
- Invasion
- Metastasis
- Non-small cell lung cancer
- Slug
- Snail
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Downregulating CD26/DPPIV by apigenin modulates the interplay between Akt and Snail/Slug signaling to restrain metastasis of lung cancer with multiple EGFR statuses. / Chang, Jer Hwa; Cheng, Chao Wen; Yang, Yi Chieh; Chen, Wan Shen; Hung, Wen Yueh; Chow, Jyh Ming; Chen, Pai Sheng; Hsiao, Michael; Lee, Wei Jiunn; Chien, Ming Hsien.
In: Journal of Experimental and Clinical Cancer Research, Vol. 37, No. 1, 199, 22.08.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Downregulating CD26/DPPIV by apigenin modulates the interplay between Akt and Snail/Slug signaling to restrain metastasis of lung cancer with multiple EGFR statuses
AU - Chang, Jer Hwa
AU - Cheng, Chao Wen
AU - Yang, Yi Chieh
AU - Chen, Wan Shen
AU - Hung, Wen Yueh
AU - Chow, Jyh Ming
AU - Chen, Pai Sheng
AU - Hsiao, Michael
AU - Lee, Wei Jiunn
AU - Chien, Ming Hsien
PY - 2018/8/22
Y1 - 2018/8/22
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
KW - Akt
KW - Apigenin
KW - CD26/dipeptidyl peptidase IV
KW - Invasion
KW - Metastasis
KW - Non-small cell lung cancer
KW - Slug
KW - Snail
UR - http://www.scopus.com/inward/record.url?scp=85051979574&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051979574&partnerID=8YFLogxK
U2 - 10.1186/s13046-018-0869-1
DO - 10.1186/s13046-018-0869-1
M3 - Article
AN - SCOPUS:85051979574
VL - 37
JO - Journal of Experimental and Clinical Cancer Research
JF - Journal of Experimental and Clinical Cancer Research
SN - 0392-9078
IS - 1
M1 - 199
ER -