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Celecoxib induces apoptosis in cervical cancer cells independent of cyclooxygenase using NF-κB as a possible target

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Abstract

Purpose

Recently, many studies have shown that celecoxib induces apoptosis in various cancer cells by different mechanisms depending on the cell type. This study examined the apoptotic effect of celecoxib in cervical cancer cells and its mechanism.

Methods

Cell viability was measured by MTT assay and apoptosis was examined by DNA fragmentation and flow cytometry. Western blotting and immunoprecipitation were used to explore various mechanisms of celecoxib-induced apoptosis. The activation of NF-κB was confirmed by EMSA.

Results

Celecoxib induced apoptosis independent of COX-2 activity. This event accompanied the activation of caspase-8 and -9 with Bid cleavage and the loss of mitochondrial membrane potential. The protective effect of caspase-8 and -9 inhibitors on celecoxib-induced apoptosis suggests the importance of caspase-8 and -9 activation in this apoptotic pathway. Fas/FADD-mediated apoptotic pathway was detected only in C33A cells, demonstrated by the immunoprecipitation of Fas-FADD in celecoxib-treated cells and the protective effect of FADD dominant negative mutant. Finally, NF-κB appeared to be involved in celecoxib-induced apoptosis, as revealed by increased NF-kB DNA binding activity in a time-dependent manner and attenuation of its proapoptotic effect by N-tosyl-L-phenylalanyl-chloromethyl ketone, an NF-kB blocker.

Conclusions

These data show that caspase-8 and -9 are involved in the apoptotic effect of celecoxib in cervical cancer cells. This requires the FADD-dependent pathway in a cell type-specific manner. In addition, NF-κB may play a key role in celecoxib-induced apoptosis.

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Abbreviations

COX:

Cyclooxygenase

NSAID:

Nonsteroidal anti-inflammatory drug

FADD:

Fas-associated death domain

TPCK:

N-tosyl-L-phenylalanyl-chloromethyl ketone

PGE2 :

Prostaglandin E2

EMSA:

Electrophoretic mobility shift assay

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Authors and Affiliations

  1. Cancer Research Institute, College of Medicine Seoul National University, Seoul, Korea

    Su-Hyeong Kim, Sang-Hyun Song, Sang-Gyun Kim, Jae Weon Kim, Yung-Jue Bang & Yong-Sang Song

  2. College of Pharmacy, Seoul National University, Seoul, Korea

    Kyung-Soo Chun, So-Young Lim, Hye-Kyung Na & Young-Joon Surh

  3. Department of Internal Medicine, Seoul National University, Seoul, Korea

    Yung-Jue Bang

  4. Department of Obstetrics and Gynecology, Cancer Research Institute, Seoul National University College of Medicine, 110-744, Seoul, Korea

    Jae Weon Kim & Yong-Sang Song

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  1. Su-Hyeong Kim
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  2. Sang-Hyun Song
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  3. Sang-Gyun Kim
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  10. Yong-Sang Song
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Correspondence to Yong-Sang Song.

Additional information

This work was supported by a grant of the Korea Health 21R&D project, Ministry of Health & Welfare, Republic of Korea (01-PJ1-PG1-01CH05-0001) and Korean 2001–2003 BK 21 Project for Medicine, Dentistry & Pharmacy.

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Kim, SH., Song, SH., Kim, SG. et al. Celecoxib induces apoptosis in cervical cancer cells independent of cyclooxygenase using NF-κB as a possible target. J Cancer Res Clin Oncol 130, 551–560 (2004). https://doi.org/10.1007/s00432-004-0567-6

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  • DOI: https://doi.org/10.1007/s00432-004-0567-6

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