title: High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs.
abstract: BACKGROUND
  Development of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenocarcinoma cells through an Akt-dependent mechanism.
  
  
  METHODS
  To elucidate the role of HMGA1 proteins in chemoresistance we analyzed resistance to conventional drugs and targeted therapies of human colon carcinoma cells (GEO) that are sensitive to the epidermal growth factor receptor inhibitor cetuximab, and express minimal levels of HMGA1 and cetuximab-resistant (GEO CR) cells expressing high HMGA1 protein levels.
  
  
  RESULTS
  GEO CR cells were less sensitive than GEO cells to cetuximab and 5-fluorouracil. GEO CR cells silenced for HMGA1 expression were more susceptible than empty vector-transfected cells to the drugs' cytotoxicity. Similar results were obtained with anaplastic thyroid carcinoma cells expressing or not HMGA1 proteins, treated with doxorubicin or the HDAC inhibitor LBH589. Finally, HMGA1 overexpression promoted the DNA-damage response and stimulated Akt phosphorylation and prosurvival signaling.
  
  
  CONCLUSIONS
  Our findings suggest that the blockage of HMGA1 expression is a promising approach to enhance cancer cell chemosensitivity, since it could increase the sensitivity of cancer cells to antineoplastic drugs by inhibiting the survival signal and DNA damage repair pathways.
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o, Università di Napoli Federico II, Via Pansini 5, 80131 Naples, Italy. daniela.dangelo@unina.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Angelo
authors.forename: Paula
authors.initials: P
authors.lastname: Mussnich
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosa
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020868:Gene Silencing; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D024003:HMGA Proteins; D004317:Doxorubicin; D020169:Caspases