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Pharmacogenomic Analysis of Adenylate Kinase‐4 Gene Expression Signature Identifies Withaferin‐A as an Anti‐Metastatic Agent in Non‐Small Cell Lung Cancer
Author(s) -
JAN YIHUA,
HSIAO MICHAEL
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.699.2
Subject(s) - withaferin a , gene signature , gene knockdown , cancer research , metastasis , cancer , lung cancer , ampk , biology , ectopic expression , cancer cell , microarray analysis techniques , medicine , gene expression , protein kinase a , kinase , pathology , apoptosis , gene , microbiology and biotechnology , biochemistry , alternative medicine , withania somnifera
Lung cancer remains the leading cause of cancer death in the world due to metastatic disseminations. So far, there are no effective therapies available to fight this fatal process. Previously, we identified adenylate kinase 4 (AK4) as a lung cancer progression marker that enhances the invasion and metastasis ability of lung cancer cells. Therefore, we queried connectivity map profiles of AK4‐associated gene expression signature and identified Withaferin‐A (WFA) as a potential agent to treat metastatic lung cancer. We found WFA potently inhibited invasion and migration of CL1‐5 and A549 cells up to 50 percent at low‐cytotoxic doses in vitro. WFA treatment also abolished the invasion activity induced by AK4 ectopic overexpression in CL1‐0 cells. Microarray analysis further revealed that differentially regulated genes upon WFA treatment were significantly enriched in gene sets annotated with cell movement and invasion of cancer cells. WFA treatment resulted in activation of stress response pathways as canonical pathway analysis indicated genes involved in ER and oxidative stress were also significantly enriched. In addition, upstream analysis showed AMPK was activated upon WFA treatment. We then validated AMPK activation was sufficient to suppress TGF‐beta‐mediated epithelial‐to‐mesenchymal transition through knockdown of AK4. Furthermore, in vivo therapeutic model showed that WFA administration significantly decreased lung orthotopic xenograft tumor growth and liver and kidney metastasis compared to the control group. These results identify WFA can be applied to treat metastatic lung cancer through repurposing approved drugs that reverse AK4‐associated gene expression signature.