Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database

Shen Jeu Won, Hsing Chih Wu, Kuan Ting Lin, Cheng Hao Yu, Yi Ting Chen, Chi Shiuan Wu, Chi Ying F. Huang, Hsiao-Sheng Liu, Chun Nan Lin, Chun Li Su

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish
Pages (from-to)81-93
Number of pages13
JournalJournal of Functional Foods
Volume16
DOIs
Publication statusPublished - 2015 Jun 1

Fingerprint

Lignans
lignans
Transcriptome
Libraries
autophagy
Databases
hepatoma
gene expression
Autophagy
Hepatocellular Carcinoma
apoptosis
cells
Apoptosis
human growth
justicidin A
Inbred NOD Mouse
SCID Mice
MAP Kinase Signaling System
organelles
Organelles

All Science Journal Classification (ASJC) codes

  • Food Science
  • Medicine (miscellaneous)
  • Nutrition and Dietetics

Cite this

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. / Discovery of molecular mechanisms of lignan justicidin A using L1000 gene expression profiles and the Library of Integrated Network-based Cellular Signatures database. In: Journal of Functional Foods. 2015 ; Vol. 16. pp. 81-93.
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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.",
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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 journalArticle

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AU - Won, Shen Jeu

AU - Wu, Hsing Chih

AU - Lin, Kuan Ting

AU - Yu, Cheng Hao

AU - Chen, Yi Ting

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AU - Su, Chun Li

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