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Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-κB and upregulation of BCL-2 and BCL-XL

Oncogene volume 25, pages 3160–3169 (2006)Cite this article

Abstract

Resistance to apoptosis is one of the important determinants of resistance to 5-fluorouracil (5-FU) in colorectal cancer cells. Human Ring-Finger homologous to Inhibitor of apoptosis protein type (hRFI) is a newly discovered gene that has been shown to inhibit death receptor-mediated apoptosis in colorectal cancer cells. However, the molecular mechanism of the inhibition of apoptosis is presently unknown. In order to investigate the molecular function of hRFI in the regulation of 5-FU-induced apoptosis in colorectal cancer cells, HCT116 cells were stably transfected with hRFI or LacZ as a control. hRFI overexpression resulted in cellular resistance to 5-FU through an inhibition of the mitochondrial apoptotic pathway and specific upregulation of Bcl-2 and Bcl-XL. Futhermore, hRFI overexpression resulted in the activation of nuclear factor-κB (NF-κB). Inhibition of NF-κB effectively reversed the resistance to apoptosis as well as the upregulation of Bcl-2 and Bcl-XL in the hRFI transfectant, indicating that the activation of NF-κB is the key mechanism for all these findings. Overexpression of hRFI in SW480 and COLO320 colorectal cancer cells similarly resulted in resistance to 5-FU with the activation of NF-κB and upregulation of Bcl-2 and Bcl-XL. hRFI might be a novel therapeutic target for gene therapy in colorectal cancer.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

COX IV:

cytochrome C oxidase IV

5-FU:

5-fluorouracil

hRFI:

human ring-finger homologous to inhibitor of apoptosis protein type

IAP:

inhibitor of apoptosis protein

IC50:

inhibitory concentration of 50%

MTS:

3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt

NF-κB:

nuclear factor-κB

PI:

propidium iodide

TNF-α:

tumor necrosis factor-α

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

XIAP:

X-chromosome-linked inhibitor of apoptosis protein

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Acknowledgements

We thank all the members of the Tumor Biology Study Group for helpful discussions, Dr K Kawai and Dr D Shida for valuable advices regarding the experimental methods and Dr K Sagawa, Dr Y Komagata, Ms C Uchikawa and Dr T Kobunai for exellent technical assistance. This work was supported in part by a Grant-in-Aid from the Ministry of Education, Science, Sports, Culture and Technology of Japan and from the Ministry of Health, Labour and Welfare, and in part by the Public Trust of Surgery Research Fund. This work was funded in part by a grant from Commission of European Communities (FI6R-CT-2003-508842 RISC-RAD).

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  1. Department of Surgical Oncology, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan

    T Konishi, S Sasaki, T Watanabe, J Kitayama & H Nagawa

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  1. T Konishi
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Correspondence to T Konishi or S Sasaki.

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Konishi, T., Sasaki, S., Watanabe, T. et al. Overexpression of hRFI inhibits 5-fluorouracil-induced apoptosis in colorectal cancer cells via activation of NF-κB and upregulation of BCL-2 and BCL-XL. Oncogene 25, 3160–3169 (2006). https://doi.org/10.1038/sj.onc.1209342

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