title: E2F1 confers anticancer drug resistance by targeting ABC transporter family members and Bcl-2 via the p73/DNp73-miR-205 circuitry.
abstract: Resistance to anti-neoplastic agents is the major cause of therapy failure, leading to disease recurrence and metastasis. E2F1 is a strong inducer of apoptosis in response to DNA damage through its capacity to activate p53/p73 death pathways. Recent evidence, however, showed that E2F1, which is aberrantly expressed in advanced malignant melanomas together with antagonistic p73 family members, drives cancer progression. Investigating mechanisms responsible for dysregulated E2F1 losing its apoptotic function, we searched for genomic signatures in primary and late clinical tumor stages to allow the prediction of downstream effectors associated with apoptosis resistance and survival of aggressive melanoma cells. We identified miR-205 as specific target of p73 and found that upon genotoxic stress, its expression is sufficiently abrogated by endogenous DNp73. Significantly, metastatic cells can be rescued from drug resistance by selective knockdown of DNp73 or overexpression of miR-205 in p73-depleted cells, leading to increased apoptosis and the reduction of tumor growth in vivo. Our data delineate an autoregulatory circuit, involving high levels of E2F1 and DNp73 to downregulate miR-205, which, in turn, controls E2F1 accumulation. Finally, drug resistance associated to this genetic signature is mediated by removing the inhibitory effect of miR-205 on the expression of Bcl-2 and the ATP-binding cassette transporters A2 (ABCA2) and A5 (ABCA5) related to multi-drug resistance and malignant progression. These results define the E2F1-p73/DNp73-miR-205 axis as a crucial mechanism for chemoresistance and, thus, as a target for metastasis prevention.
authors.affiliation: Department of Vectorology and Experimental Gene Therapy, Biomedical Research Center, Rostock University Medicine, Rostock, Germany.
authors.forename: Vijay
authors.initials: V
authors.lastname: Alla
authors.forename: Bhavani S
authors.initials: BS
authors.lastname: Kowtharapu
authors.forename: David
authors.initials: D
authors.lastname: Engelmann
authors.forename: Stephan
authors.initials: S
authors.lastname: Emmrich
authors.forename: Ulf
authors.initials: U
authors.lastname: Schmitz
authors.forename: Marc
authors.initials: M
authors.lastname: Steder
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003513:Cycloheximide; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D035683:MicroRNAs; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C418186:ABCA2 protein, human; C471294:ABCA5 protein, human; C493753:E2F1 protein, human; C534425:MIR205, human; C495901:TP53 protein, human; C000606460:TP73 protein, human