Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression

Inhibition of c-Abl by the tumor suppressor gene product Fus1

J. Lin, T. Sun, L. Ji, W. Deng, J. Roth, J. Minna, R. Arlinghaus

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

In lung cancer, frequent loss of one allele of chromosome 3p is seen in both small cell lung cancer and non-small cell lung cancer (NSCLC), providing evidence of tumor suppressor genes (TSGs) in this chromosomal region. The mechanism of Fus1 tumor suppressor activity is unknown. We have found that a Fus1 peptide inhibits the Abl tyrosine kinase in vitro (IC50 35 μM). The inhibitory Fus1 sequence was derived from a region that was deleted in a mutant FUS1 gene (FUS1 (1-80)) detected in some lung cancer cell lines. Importantly, a stearic acid-modified form of this peptide was required for the inhibition, but stearic acid alone was not inhibitory. Two NSCLC cell lines, which lack expression of wild-type Fus1, contain activated c-Abl. Forced expression of an inducible FUS1 cDNA in H1299 NSCLC cells decreased levels of activated c-Abl and inhibited its tyrosine kinase activity. Similarly, treatment of c-Abl immune complexes with the inhibitory Fus1 peptide also reduced the level of c-Abl in these immune complexes. The size and number of colonies of the NSCLC cell line, H1299, in soft agar was strongly inhibited by the Abl kinase inhibitor imatinib mesylate. Co-expression of FUS1 and c-ABL in COS1 cells blocked activation of c-Abl tyrosine kinase. In contrast, co-expression of mutant FUS1 (1-80) with c-ABL had little inhibitory activity against c-Abl. These findings provide strong evidence that c-Abl is a possible target in NSCLC patients that have reduced expression of Fus1 in their tumor cells.

Original languageEnglish (US)
Pages (from-to)6989-6996
Number of pages8
JournalOncogene
Volume26
Issue number49
DOIs
StatePublished - Oct 25 2007

Fingerprint

Tumor Suppressor Genes
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Antigen-Antibody Complex
Cell Line
Peptides
Lung Neoplasms
Small Cell Lung Carcinoma
Inhibitory Concentration 50
Agar
Neoplasms
Phosphotransferases
Complementary DNA
Chromosomes
Alleles
Genes
stearic acid
Therapeutics

Keywords

  • c-Abl
  • FUS1
  • Imatinib
  • Lung cancer
  • NSCLC

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Oncogenic activation of c-Abl in non-small cell lung cancer cells lacking FUS1 expression : Inhibition of c-Abl by the tumor suppressor gene product Fus1. / Lin, J.; Sun, T.; Ji, L.; Deng, W.; Roth, J.; Minna, J.; Arlinghaus, R.

In: Oncogene, Vol. 26, No. 49, 25.10.2007, p. 6989-6996.

Research output: Contribution to journalArticle

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abstract = "In lung cancer, frequent loss of one allele of chromosome 3p is seen in both small cell lung cancer and non-small cell lung cancer (NSCLC), providing evidence of tumor suppressor genes (TSGs) in this chromosomal region. The mechanism of Fus1 tumor suppressor activity is unknown. We have found that a Fus1 peptide inhibits the Abl tyrosine kinase in vitro (IC50 35 μM). The inhibitory Fus1 sequence was derived from a region that was deleted in a mutant FUS1 gene (FUS1 (1-80)) detected in some lung cancer cell lines. Importantly, a stearic acid-modified form of this peptide was required for the inhibition, but stearic acid alone was not inhibitory. Two NSCLC cell lines, which lack expression of wild-type Fus1, contain activated c-Abl. Forced expression of an inducible FUS1 cDNA in H1299 NSCLC cells decreased levels of activated c-Abl and inhibited its tyrosine kinase activity. Similarly, treatment of c-Abl immune complexes with the inhibitory Fus1 peptide also reduced the level of c-Abl in these immune complexes. The size and number of colonies of the NSCLC cell line, H1299, in soft agar was strongly inhibited by the Abl kinase inhibitor imatinib mesylate. Co-expression of FUS1 and c-ABL in COS1 cells blocked activation of c-Abl tyrosine kinase. In contrast, co-expression of mutant FUS1 (1-80) with c-ABL had little inhibitory activity against c-Abl. These findings provide strong evidence that c-Abl is a possible target in NSCLC patients that have reduced expression of Fus1 in their tumor cells.",
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