Id-1B, an alternatively spliced isoform of the inhibitor of differentiation-1, impairs cancer cell malignancy through inhibition of proliferation and angiogenesis

P. Nguewa, I. Manrique, R. Díaz, M. Redrado, R. Parrondo, Carlos Perez-Stable, A. Calvo

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)151-162
Number of pages12
JournalCurrent Molecular Medicine
Volume14
Issue number1
StatePublished - Jan 14 2014

Fingerprint

Tumors
Protein Isoforms
Cells
Radiotherapy
Cell growth
Cell death
Neoplasms
Cyclin A
Chemotherapy
Cell proliferation
Alternative Splicing
Lung
Microarrays
Prostatic Neoplasms
Cell Death
Dosimetry
Growth
Assays
Transcription Factors
Genes

Keywords

  • Angiogenesis
  • Id-1
  • Lung cancer
  • Prostate cancer
  • Radiotherapy
  • Splicing

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine

Cite this

Id-1B, an alternatively spliced isoform of the inhibitor of differentiation-1, impairs cancer cell malignancy through inhibition of proliferation and angiogenesis. / Nguewa, P.; Manrique, I.; Díaz, R.; Redrado, M.; Parrondo, R.; Perez-Stable, Carlos; Calvo, A.

In: Current Molecular Medicine, Vol. 14, No. 1, 14.01.2014, p. 151-162.

Research output: Contribution to journalArticle

@article{97aac4bb63b744a19af2860da7ad5f39,
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.",
keywords = "Angiogenesis, Id-1, Lung cancer, Prostate cancer, Radiotherapy, Splicing",
author = "P. Nguewa and I. Manrique and R. D{\'i}az and M. Redrado and R. Parrondo and Carlos Perez-Stable and A. Calvo",
year = "2014",
month = "1",
day = "14",
language = "English",
volume = "14",
pages = "151--162",
journal = "Current Molecular Medicine",
issn = "1566-5240",
publisher = "Bentham Science Publishers B.V.",
number = "1",

}

TY - JOUR

T1 - Id-1B, an alternatively spliced isoform of the inhibitor of differentiation-1, impairs cancer cell malignancy through inhibition of proliferation and angiogenesis

AU - Nguewa, P.

AU - Manrique, I.

AU - Díaz, R.

AU - Redrado, M.

AU - Parrondo, R.

AU - Perez-Stable, Carlos

AU - Calvo, A.

PY - 2014/1/14

Y1 - 2014/1/14

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - Id-1

KW - Lung cancer

KW - Prostate cancer

KW - Radiotherapy

KW - Splicing

UR - http://www.scopus.com/inward/record.url?scp=84891851424&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891851424&partnerID=8YFLogxK

M3 - Article

C2 - 24295493

AN - SCOPUS:84891851424

VL - 14

SP - 151

EP - 162

JO - Current Molecular Medicine

JF - Current Molecular Medicine

SN - 1566-5240

IS - 1

ER -