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

Oncogene volume 23, pages 8731–8742 (2004)Cite this article

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.

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Abbreviations

GC:

gastric cancer

NF-κB:

nuclear factor-κB

IκB:

inhibitory subunit of NF-κB

IKK:

IκBα kinase

MAPK:

mitogen-activated protein kinase

PI 3-kinase:

phosphatidylinositol 3-kinase

RT–PCR:

reverse transcription–polymerase chain reaction

FACS:

fluorescence-activated cell sorting

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Acknowledgements

We thank Dr Z-F Chang (Institute of Biochemistry and Molecular Biology, National Taiwan University, Taiwan) for constructive suggestions. This work is supported in part by NSC91-3112-P-001-024-Y and Chen Shuyi Cancer Foundation.

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Authors and Affiliations

  1. Graduate Institute of Life Sciences, National Defense Medical Center, ROC, Taiwan

    Ching-Ann Liu

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, ROC, Taiwan

    Mei-Jung Wang & Jeou-Yuan Chen

  3. Department of Medical Research and Education, ROC, Taiwan

    Chin-Wen Chi

  4. Department of Surgery, Veterans General Hospital, Taipei, ROC, Taiwan

    Chew-Wun Wu

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Correspondence to Jeou-Yuan Chen.

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Liu, CA., Wang, MJ., Chi, CW. et al. Rho/Rhotekin-mediated NF-κB activation confers resistance to apoptosis. Oncogene 23, 8731–8742 (2004). https://doi.org/10.1038/sj.onc.1208106

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