Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch

Gitanjali Jayachandran, Ji Ichiro Sazaki, Masahiko Nishizaki, Kai Xu, Luc Girard, John D. Minna, Jack A. Roth, Lin Ji

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The fragile histidine triad (FHIT) gene has been shown to function as a tumor suppressor gene in vitro and in vivo. However, the mechanism of its action is still largely unknown. To elucidate the molecular mechanism and biological pathway in FHIT-mediated tumor suppression, we used a complementary gene and protein expression profiling with DNA microarray and ProteinChip technologies to quantitatively monitor cellular changes in gene and protein expression and discover the molecular targets of FHIT in non-small cell lung carcinoma (NSCLC) cells. The Ras/Rho signaling pathway was identified as one of the unique biological pathways associated with FHIT activity. A significantly down-regulated expression of genes and proteins of multiple key components in the Ras/Rho GTPases molecular switch, including Ran, Rab, Rac, Rap, and Ral, was observed on gene and protein expression profiles and further validated by Western blot analysis. Ectopic activation of FHIT in FHIT-deficient H1299 cells also significantly reduced the invasive potential of tumor cells by down-regulating expression of RhoC, a potential marker of tumor cell invasion and metastases. A simultaneous knockdown of the expression of several key Ras/Rho signaling molecules using gene-specific small interfering RNAs (RHO-siRNA) targeting selected Rab11, Rac1, and Rap1 genes significantly inhibited tumor cell growth and induced apoptosis in NSCLC cells in vitro, and a local injection of RHO-siRNAs complexed with N-[1-(2,3-dioleoyloxyl)propyl]-N, N,N-trimethylammoniummethyl sulfate:cholesterol nanoparticles inhibited tumor growth in A549 tumor xenografts in mice, mimicking the AdFHIT-mediated tumor-suppressing effect. These results suggest a new role of FHIT in down-regulating the Ras/Rho GTPase-associated oncogenic signaling pathway.

Original languageEnglish
Pages (from-to)10379-10388
Number of pages10
JournalCancer Research
Volume67
Issue number21
DOIs
Publication statusPublished - Nov 1 2007
Externally publishedYes

Fingerprint

ras Proteins
rho GTP-Binding Proteins
Histidine
Lung Neoplasms
Neoplasms
Non-Small Cell Lung Carcinoma
Small Interfering RNA
Proteins
Far-Western Blotting
Genes
Protein Array Analysis
Gene Expression Profiling
Tumor Biomarkers
Growth
Oligonucleotide Array Sequence Analysis
Tumor Suppressor Genes
Transcriptome
Heterografts
Nanoparticles
Apoptosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. / Jayachandran, Gitanjali; Sazaki, Ji Ichiro; Nishizaki, Masahiko; Xu, Kai; Girard, Luc; Minna, John D.; Roth, Jack A.; Ji, Lin.

In: Cancer Research, Vol. 67, No. 21, 01.11.2007, p. 10379-10388.

Research output: Contribution to journalArticle

Jayachandran, Gitanjali ; Sazaki, Ji Ichiro ; Nishizaki, Masahiko ; Xu, Kai ; Girard, Luc ; Minna, John D. ; Roth, Jack A. ; Ji, Lin. / Fragile histidine triad-mediated tumor suppression of lung cancer by targeting multiple components of the Ras/Rho GTPase molecular switch. In: Cancer Research. 2007 ; Vol. 67, No. 21. pp. 10379-10388.
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