title: Interference with energy metabolism by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside induces HPV suppression in cervical carcinoma cells and apoptosis in the absence of LKB1.
abstract: Carcinogenesis is a dynamic and stepwise process, which is accompanied by a variety of somatic and epigenetic alterations in response to a changing microenvironment. Hypoxic conditions will select for cells that have adjusted their metabolic profile and can maintain proliferation by successfully competing for scarce nutritional and oxygen resources. In the present study we have investigated the effects of energy depletion in the context of HPV (human papillomavirus)-induced pathogenesis. We show that cervical carcinoma cell lines are susceptible to undergoing either growth arrest or cell death under conditions of metabolic stress induced by AICAR (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside), a known activator of the AMPK (AMP-activated protein kinase). Our results reveal that AICAR treatment leads to a reduced binding affinity of the transcription factor AP-1 (activator protein-1) and in turn to a selective suppression of HPV transcription. Moreover, the outcome of AICAR on proliferation and survival was dependent on p53 activation and the presence of LKB1, the major upstream kinase of AMPK. Using non-malignant LKB1-expressing somatic cell hybrids, which lose expression after tumorigenic segregation, as well as small interfering RNA LKB1 knockdown approaches, we could further demonstrate that expression of LKB1 protects cells from cytotoxicity induced by agents which modulate the ATP/AMP ratio. Since simulation of low energy status can selectively eradicate LKB1-negative cervical carcinoma cells, AICAR may represent a novel drug in the treatment of cervical cancer.
authors.affiliation: Angewandte Tumorvirologie, Abteilung Virale Transformationsmechanismen, Deutsches Krebsforschungszentrum, Heidelberg 69120, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Nafz
authors.forename: Johanna
authors.initials: J
authors.lastname: De-Castro Arce
authors.forename: Verena
authors.initials: V
authors.lastname: Fleig
authors.forename: Andrea
authors.initials: A
authors.lastname: Patzelt
authors.forename: Sybille
authors.initials: S
authors.lastname: Mazurek
authors.forename: Frank
authors.initials: F
authors.lastname: Rösl
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003847:Deoxyglucose / Q000494:pharmacology; D015536:Down-Regulation; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006367:HeLa Cells; D052161:Human papillomavirus 18 / Q000187:drug effects*; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D002583:Uterine Cervical Neoplasms / Q000821:virology
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; D012263:Ribonucleosides; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases