Abstract
Justicidin A (JA), a novel arylnaphthalide lignan, was previously found to reduce the growth of human hepatocellular carcinoma cells (HCC), Hep 3B cells, in NOD-SCID mice via induction of apoptosis. Here, using L1000 microarray profiling obtained from JA-treated HCC cells, the z-score signatures of JA exhibited positive connectivity to known autophagy inducers among 3122 compounds from the Library of Integrated Network-based Cellular Signatures database. JA-induced autophagy in HCC Hep 3B cells was confirmed by formation of acidic vesicular organelles and an increase in the expression of LC3-II and LAMP2a. JA-induced autophagic flux was demonstrated by accumulation of LC3-II and LAMP2a, as well as a decrease in colocalization of LC3 and LAMP2a puncta in the presence of autophagy inhibitor bafilomycin A1. Administration of bafilomycin A1 also demonstrated that JA-induced autophagy suppressed apoptosis. Activation of Ras/MEK/ERK pathway was observed. Following administration of apoptosis inhibitor zVAD, it was found that JA-induced apoptosis did not affect JA-induced autophagy. It is noteworthy that addition of JA promoted chemosensitivity of sorafenib, the only FDA-approved targeted therapy for advanced HCC. The results demonstrate the effectiveness of this novel strategy for rapid discovery of molecular actions of small molecules and suggest the applications of JA in HCC treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 81-93 |
| Number of pages | 13 |
| Journal | Journal of Functional Foods |
| Volume | 16 |
| DOIs | |
| Publication status | Published - 2015 Jun 1 |
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All Science Journal Classification (ASJC) codes
- Food Science
- Medicine (miscellaneous)
- Nutrition and Dietetics
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Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database. / Won, Shen Jeu; Wu, Hsing Chih; Lin, Kuan Ting; Yu, Cheng Hao; Chen, Yi Ting; Wu, Chi Shiuan; Huang, Chi Ying F.; Liu, Hsiao-Sheng; Lin, Chun Nan; Su, Chun Li.
In: Journal of Functional Foods, Vol. 16, 01.06.2015, p. 81-93.Research output: Contribution to journal › Article
TY - JOUR
T1 - Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database
AU - Won, Shen Jeu
AU - Wu, Hsing Chih
AU - Lin, Kuan Ting
AU - Yu, Cheng Hao
AU - Chen, Yi Ting
AU - Wu, Chi Shiuan
AU - Huang, Chi Ying F.
AU - Liu, Hsiao-Sheng
AU - Lin, Chun Nan
AU - Su, Chun Li
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Justicidin A (JA), a novel arylnaphthalide lignan, was previously found to reduce the growth of human hepatocellular carcinoma cells (HCC), Hep 3B cells, in NOD-SCID mice via induction of apoptosis. Here, using L1000 microarray profiling obtained from JA-treated HCC cells, the z-score signatures of JA exhibited positive connectivity to known autophagy inducers among 3122 compounds from the Library of Integrated Network-based Cellular Signatures database. JA-induced autophagy in HCC Hep 3B cells was confirmed by formation of acidic vesicular organelles and an increase in the expression of LC3-II and LAMP2a. JA-induced autophagic flux was demonstrated by accumulation of LC3-II and LAMP2a, as well as a decrease in colocalization of LC3 and LAMP2a puncta in the presence of autophagy inhibitor bafilomycin A1. Administration of bafilomycin A1 also demonstrated that JA-induced autophagy suppressed apoptosis. Activation of Ras/MEK/ERK pathway was observed. Following administration of apoptosis inhibitor zVAD, it was found that JA-induced apoptosis did not affect JA-induced autophagy. It is noteworthy that addition of JA promoted chemosensitivity of sorafenib, the only FDA-approved targeted therapy for advanced HCC. The results demonstrate the effectiveness of this novel strategy for rapid discovery of molecular actions of small molecules and suggest the applications of JA in HCC treatment.
AB - Justicidin A (JA), a novel arylnaphthalide lignan, was previously found to reduce the growth of human hepatocellular carcinoma cells (HCC), Hep 3B cells, in NOD-SCID mice via induction of apoptosis. Here, using L1000 microarray profiling obtained from JA-treated HCC cells, the z-score signatures of JA exhibited positive connectivity to known autophagy inducers among 3122 compounds from the Library of Integrated Network-based Cellular Signatures database. JA-induced autophagy in HCC Hep 3B cells was confirmed by formation of acidic vesicular organelles and an increase in the expression of LC3-II and LAMP2a. JA-induced autophagic flux was demonstrated by accumulation of LC3-II and LAMP2a, as well as a decrease in colocalization of LC3 and LAMP2a puncta in the presence of autophagy inhibitor bafilomycin A1. Administration of bafilomycin A1 also demonstrated that JA-induced autophagy suppressed apoptosis. Activation of Ras/MEK/ERK pathway was observed. Following administration of apoptosis inhibitor zVAD, it was found that JA-induced apoptosis did not affect JA-induced autophagy. It is noteworthy that addition of JA promoted chemosensitivity of sorafenib, the only FDA-approved targeted therapy for advanced HCC. The results demonstrate the effectiveness of this novel strategy for rapid discovery of molecular actions of small molecules and suggest the applications of JA in HCC treatment.
UR - http://www.scopus.com/inward/record.url?scp=84937545349&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937545349&partnerID=8YFLogxK
U2 - 10.1016/j.jff.2015.04.025
DO - 10.1016/j.jff.2015.04.025
M3 - Article
AN - SCOPUS:84937545349
VL - 16
SP - 81
EP - 93
JO - Journal of Functional Foods
JF - Journal of Functional Foods
SN - 1756-4646
ER -