title: The impairment of the High Mobility Group A (HMGA) protein function contributes to the anticancer activity of trabectedin.
abstract: Trabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine origin with potent antitumour activity both in vitro and in vivo. It interacts with the minor groove of DNA, interfering with transcriptional activity and DNA repair pathways. Here, we report a novel mechanism by which trabectedin exerts its cytotoxic effects on carcinoma cells. It is based on its ability to impair the function of the High-Mobility Group A (HMGA) proteins. These proteins have a key role in cell transformation, and their overexpression is a common feature of human malignant neoplasias, representing a poor prognostic index often correlated to anti-cancer drug resistance. They bind the minor groove of DNA, alter chromatin structure and, thus, regulate the transcription of several genes by enhancing or suppressing the activity of transcription factors. We first report that trabectedin has a higher cytotoxic effect on thyroid and colon carcinoma cells expressing abundant levels of HMGAs in comparison with cells not expressing them. Then, we have shown that trabectedin treatment displaces HMGA proteins from the HMGA-responsive promoters, including ATM promoter, impairing their transcriptional activity. Finally, we report a synergism between Ionising Radiations and trabectedin treatment restricted to the HMGA-overexpressing cancer cells. This result might have important clinical implications since it would suggest the use of trabectedin for the treatment of neoplasias expressing abundant HMGA levels that are frequently associated to chemoresistance and poor prognosis.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Angelo
authors.forename: Eleonora
authors.initials: E
authors.lastname: Borbone
authors.forename: Dario
authors.initials: D
authors.lastname: Palmieri
authors.forename: Sarah
authors.initials: S
authors.lastname: Uboldi
authors.forename: Francesco
authors.initials: F
authors.lastname: Esposito
authors.forename: Roberta
authors.initials: R
authors.lastname: Frapolli
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: D'Incalci
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D000077606:Trabectedin; D015533:Transcriptional Activation / Q000187:drug effects; D054928:Validation Studies as Topic
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D024003:HMGA Proteins; D011838:Radiation-Sensitizing Agents; D044005:Tetrahydroisoquinolines; D004247:DNA; D000077606:Trabectedin