title: Id-1B, an alternatively spliced isoform of the inhibitor of differentiation-1, impairs cancer cell malignancy through inhibition of proliferation and angiogenesis.
abstract: Id-1 is a member of the helix-loop-helix family of proteins that regulates the activity of transcription factors to suppress cellular differentiation and to promote cell growth. Overexpression of Id-1 in tumor cells correlates with increased malignancy and resistance to chemotherapy and radiotherapy. Id-1B is an isoform generated by alternative splicing that differs from the classical Id-1 in the 13-C-terminal amino acids, whose function is at present unknown. We have studied the role of Id-1B in cancer and its expression in healthy/malignant lung tissues. Overexpression of Id-1B in A549 lung and PC3 prostate cancer cells reduced anchorage-dependent and independent proliferation and clonogenic potential. Moreover, it increased the proportion of cells in the G0/G1 phase of the cell cycle and p27 levels, while reduced phospho-Erk and cyclin A levels. Through microarray analysis, we identified genes involved in cell growth and proliferation that are specifically deregulated as a consequence of Id-1B overexpression, including IGF2, BMP4, Id2, GATA3, EREG and AREG. Id-1B overexpressing cells that were treated with 4Gy irradiation dose were significantly less resistant to cell death. In vivo assays demonstrated that tumors with high Id-1B levels exhibited less growth (p<0.01), metabolic activity (glucose uptake) and angiogenesis (p<0.05) compared to tumors with low Id-1B expression; mice survival was significantly extended (p<0.05). Quantification by qRT-PCR revealed that expression of Id-1B was significantly lower (p<0.01) in human lung tumors compared to their matched nonmalignant counterparts. In conclusion, our results demonstrate that Id-1B decreases the malignancy of lung and prostate cancer cells, sensitizes them to radiotherapy-induced cell death, and counteracts the protumorigenic role of the classical form of Id-1.
authors.forename: P
authors.initials: P
authors.lastname: Nguewa
authors.forename: I
authors.initials: I
authors.lastname: Manrique
authors.forename: R
authors.initials: R
authors.lastname: Díaz
authors.forename: M
authors.initials: M
authors.lastname: Redrado
authors.forename: R
authors.initials: R
authors.lastname: Parrondo
authors.forename: C
authors.initials: C
authors.lastname: Perez-Stable
authors.affiliation: Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain. acalvo@unav.es.
authors.forename: A
authors.initials: A
authors.lastname: Calvo
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051798:Inhibitor of Differentiation Protein 1; D016159:Tumor Suppressor Protein p53