Id-1B, an Alternatively Spliced Isoform of the Inhibitor of Differentiation-1, Impairs Cancer Cell Malignancy Through Inhibition of Proliferation and Angiogenesis

Author(s): P. Nguewa, I. Manrique, R. Díaz, M. Redrado, R. Parrondo, C. Perez-Stable, A. Calvo.

Journal Name: Current Molecular Medicine

Volume 14 , Issue 1 , 2014

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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.

Keywords: Angiogenesis, Id-1, lung cancer, prostate cancer, radiotherapy, splicing.

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Article Details

VOLUME: 14
ISSUE: 1
Year: 2014
Page: [151 - 162]
Pages: 12
DOI: 10.2174/1566524013666131203100643
Price: $58

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