title: Repression of integrin-linked kinase by antidiabetes drugs through cross-talk of PPARγ- and AMPKα-dependent signaling: role of AP-2α and Sp1.
abstract: Nasopharyngeal carcinoma (NPC) is one of the most common cancers of the head and neck, particularly in Southern China and Southeast Asia with high treatment failure due to the development of local recurrence and distant metastasis. The molecular mechanisms related to the progression of NPC have not been fully understood. In this study, we showed that antidiabetes drugs rosiglitazone and metformin inhibit NPC cell growth through reducing the expression of integrin-linked kinase (ILK). Blockade of PPARγ and AMPKα overcame the effects of rosiglitazone and metformin on ILK protein. Importantly, overexpression of ILK abrogated the effect of rosiglitazone and metformin on NPC cell growth. Furthermore, these agents reduced ILK promoter activity, which was not observed in AP-2α, but not Sp1 site mutation in ILK gene promoter. In addition, silencing of AP-2α or overexpression of Sp1 reversed the effect of these agents on ILK protein expression and cell growth. Chromatin immunoprecipitation (ChIP) assay showed that rosiglitazone induced AP-2α, while metformin reduced Sp1 protein binding to the DNA sequences in the ILK gene promoter. Intriguingly, overexpression of Sp1 abolished the effect of rosiglitazone on AP-2α protein expression. Collectively, we show that rosiglitazone and metformin inhibit ILK gene expression through PPARγ- and AMPKα-dependent signaling pathways that are involved in the regulation of AP-2α and Sp1 protein expressions. The effect of combination of rosiglitazone and metformin demonstrates greater extent than single agent alone. The cross-talk of PPARγ and AMPKα signaling enhances the synergistic effects of rosiglitazone and metformin. This study unveils novel mechanisms by which oral antidiabetes drugs inhibit the growth of human NPC cells.
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510120, China. Electronic address: swhan2010@live.com.
authors.forename: Swei Sunny
authors.initials: SS
authors.lastname: Hahn
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Shunyu
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Laboratory of Tumor Molecular Biology and Targeted Therapies, University of Guangzhou Traditional Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province 510120, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, 00852, Hong Kong, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D002277:Carcinoma; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D009154:Mutation; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy; D047495:PPAR gamma / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*; D045162:Thiazolidinediones / Q000494:pharmacology; D050656:Transcription Factor AP-2 / Q000096:biosynthesis / Q000235:genetics*; D000099200:Scaffold Protein ILK
chemical_list: D055372:AMP-Activated Protein Kinases; D007004:Hypoglycemic Agents; D008687:Metformin; D047495:PPAR gamma; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D000077154:Rosiglitazone; D016329:Sp1 Transcription Factor; D045162:Thiazolidinediones; D050656:Transcription Factor AP-2; D000099200:Scaffold Protein ILK
keywords: AMPKα; AP-2α; ILK; Nasopharyngeal carcinoma cells; PPARγ; Sp1