Title:Id-1B, an Alternatively Spliced Isoform of the Inhibitor of Differentiation-1, Impairs Cancer Cell Malignancy Through Inhibition of Proliferation and Angiogenesis
Volume: 14
Issue: 1
Author(s): P. Nguewa, I. Manrique, R. Díaz, M. Redrado, R. Parrondo, C. Perez-Stable and A. Calvo
Affiliation:
Keywords:
Angiogenesis, Id-1, lung cancer, prostate cancer, radiotherapy, splicing.
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.
