Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells

Takushi Namba, Tatsuya Hoshino, Ken Ichiro Tanaka, Shinji Tsutsumi, Tomoaki Ishihara, Shinji Mima, Keitarou Suzuki, Satoshi Ogawa, Tohru Mizushima

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Induction of apoptosis by nonsteroidal anti-inflammatory drugs, such as celecoxib, is involved in their antitumor activity. An endoplasmic reticulum chaperone, 150-kDa oxygen-regulated protein (ORP150) is essential for the maintenance of cellular viability under hypoxia and is reported to be overexpressed in clinically isolated tumors. We here found that ORP150 was up-regulated by celecoxib in human gastric carcinoma cells. In conjunction with the suppression of tumor growth, orally administered celecoxib up-regulated ORP150 in xenograft tumors. Both the ATF4 and ATF6 pathways were activated by celecoxib, and suppression of ATF4 and ATF6 mRNA expression by small interfering RNA (siRNA) inhibited the celecoxib-dependent up-regulation of ORP150. Celecoxib administration led to an increase in the intracellular concentration of Ca2+, whereas 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′- tetraacetic acid-acetoxymethyl ester, an intracellular Ca2+ chelator, inhibited the up-regulation of ORP150 and the activation of the ATF4 and ATF6 pathways. These results suggest that these Ca2+-activated pathways are involved in the celecoxib-mediated up-regulation of ORP150. Clones overexpressing ORP150 were less susceptible to celecoxib-induced, but not staurosporine-induced, apoptosis and displayed less up-regulation of C/EBP homologous transcription factor (CHOP), a transcription factor with apoptosis-inducing activity. In contrast, siRNA for ORP150 stimulated apoptosis and expression of CHOP in the presence of celecoxib but not staurosporine. These results suggest that up-regulation of ORP150 in cancer cells inhibits celecoxib-induced apoptosis, thereby decreasing the potential antitumor activity of celecoxib.

Original languageEnglish
Pages (from-to)860-870
Number of pages11
JournalMolecular Pharmacology
Volume71
Issue number3
DOIs
Publication statusPublished - 2007 Mar
Externally publishedYes

Fingerprint

Celecoxib
Stomach
Up-Regulation
Carcinoma
Apoptosis
Staurosporine
Small Interfering RNA
Neoplasms
oxygen-regulated proteins
Transcription Factor CHOP

ASJC Scopus subject areas

  • Pharmacology

Cite this

Namba, T., Hoshino, T., Tanaka, K. I., Tsutsumi, S., Ishihara, T., Mima, S., ... Mizushima, T. (2007). Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells. Molecular Pharmacology, 71(3), 860-870. https://doi.org/10.1124/mol.106.027698

Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells. / Namba, Takushi; Hoshino, Tatsuya; Tanaka, Ken Ichiro; Tsutsumi, Shinji; Ishihara, Tomoaki; Mima, Shinji; Suzuki, Keitarou; Ogawa, Satoshi; Mizushima, Tohru.

In: Molecular Pharmacology, Vol. 71, No. 3, 03.2007, p. 860-870.

Research output: Contribution to journalArticle

Namba, T, Hoshino, T, Tanaka, KI, Tsutsumi, S, Ishihara, T, Mima, S, Suzuki, K, Ogawa, S & Mizushima, T 2007, 'Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells', Molecular Pharmacology, vol. 71, no. 3, pp. 860-870. https://doi.org/10.1124/mol.106.027698
Namba, Takushi ; Hoshino, Tatsuya ; Tanaka, Ken Ichiro ; Tsutsumi, Shinji ; Ishihara, Tomoaki ; Mima, Shinji ; Suzuki, Keitarou ; Ogawa, Satoshi ; Mizushima, Tohru. / Up-regulation of 150-kDa oxygen-regulated protein by celecoxib in human gastric carcinoma cells. In: Molecular Pharmacology. 2007 ; Vol. 71, No. 3. pp. 860-870.
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