Rho/Rhotekin-mediated NF-κB activation confers resistance to apoptosis

Ching-Ann Liu, Mei-Jung Wang, Chin-Wen Chi, Chew-Wun Wu, Jeou-Yuan Chen

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68 Citations (Scopus)

Abstract

Rhotekin (RTKN), the gene coding for the Rho effector, RTKN, was shown to be overexpressed in human gastric cancer (GC). In this study, we further showed that RTKN is expressed at a low level in normal cells and is overexpressed in many cancer-derived cell lines. The function of RTKN as an effector protein in Rho GTPase-mediated pathways regulating apoptosis was investigated. By transfection and expression of RTKN in cells that expressed endogenous RTKN at a low basal level, we showed that RTKN overexpression conferred cell resistance to apoptosis induced by serum deprivation or treatment with sodium butyrate, and the increased resistance correlated to the level of RTKN. Conversely, reducing RTKN expression by small interfering RNAs greatly sensitized cells to apoptosis. The RTKN-mediated antiapoptotic effect was blocked by the nuclear factor-κB (NF-κB) inhibitors, curcumin or parthenolide, but not by the phosphatidylinositol 3′-OH-kinase inhibitor, LY294002, or the MAP kinase inhibitor, PD98059. Reporter gene assays and electrophoretic mobility shift assay confirmed that RTKN overexpression led to constitutive activation of NF-κB through the phosphorylation of IκB by IKKβ. By using the RTKN truncation mutants, we showed that RTKN mediated Rho activity eliciting signaling pathway to activate NF-κB, with a concomitant induction of expression of the NF-κB antiapoptotic genes, cIAP-2, BCl-xL, A1, and A20. Consistent with these data, RTKN-expressing cells showed increased chemoresistance to 5-fluorouracil and paclitaxol, and the resistance was greatly attenuated by NF-κB inhibitor. In conclusion, overactivated Rho/ RTKN/NF-κB signaling pathway through overexpression of RTKN may play a key role in gastric tumorigenesis by conferring cells resistance to apoptosis, and this signaling pathway may serve as an important target for novel therapeutic approaches to the treatment of human GC.
Original languageEnglish
Pages (from-to)8731-8742
Number of pages12
JournalOncogene
Volume23
Issue number54
DOIs
Publication statusPublished - 2004
Externally publishedYes

Keywords

  • Antiapoptosis
  • Gastric cancer
  • Nuclear factor-κB
  • Rho GTPases
  • Rhotekin
  • 2 (2 amino 3 methoxyphenyl)chromone
  • 2 morpholino 8 phenylchromone
  • butyric acid
  • curcumin
  • fluorouracil
  • I kappa B
  • immunoglobulin enhancer binding protein
  • mitogen activated protein kinase inhibitor
  • paclitaxel
  • parthenolide
  • phosphatidylinositol 3 kinase inhibitor
  • protein
  • Rho factor
  • Rho guanine nucleotide binding protein
  • rhotekin
  • small interfering RNA
  • unclassified drug
  • A1 gene
  • a20 gene
  • apoptosis
  • article
  • assay
  • bcl xl gene
  • cancer cell culture
  • ciap 2 gene
  • controlled study
  • correlation analysis
  • gel mobility shift assay
  • gene
  • gene expression
  • gene function
  • gene induction
  • gene overexpression
  • genetic transfection
  • human
  • human cell
  • mutant
  • nucleotide sequence
  • priority journal
  • protein phosphorylation
  • regulatory mechanism
  • reporter gene
  • rhotekin gene
  • serum
  • signal transduction
  • Amino Acid Sequence
  • Apoptosis
  • Base Sequence
  • Cell Line, Tumor
  • DNA Primers
  • Electrophoretic Mobility Shift Assay
  • Flow Cytometry
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Reverse Transcriptase Polymerase Chain Reaction
  • rho GTP-Binding Proteins

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  • Cite this

    Liu, C-A., Wang, M-J., Chi, C-W., Wu, C-W., & Chen, J-Y. (2004). Rho/Rhotekin-mediated NF-κB activation confers resistance to apoptosis. Oncogene, 23(54), 8731-8742. https://doi.org/10.1038/sj.onc.1208106