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Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells

Oncogene volume 27, pages 3032–3044 (2008)Cite this article

Abstract

The role of cyclooxygenase-2 (COX-2) in cancer remains controversial. Using cervical carcinoma cells (HeLa), the present study investigates the involvement of COX-2 in apoptosis elicited by the chemotherapeutics paclitaxel, cisplatin and 5-fluorouracil. Each compound led to a profound induction of COX-2 expression and prostaglandin (PG) synthesis, accompanied by a substantial decrease of viability and enhanced apoptosis. Cells were significantly less sensitive to apoptotic death when either COX-2 expression or its activity was suppressed by small-interfering RNA (siRNA) and by the selective COX-2 inhibitor NS-398, respectively. Experiments performed to clarify how COX-2 leads to apoptosis revealed a profound proapoptotic action of PGD2 and its dehydration product, 15-deoxy-Δ12,14 PGJ2 (15d-PGJ2). In line with these findings, chemotherapeutics-induced apoptosis was prevented by siRNA targeting lipocalin-type PGD synthase (L-PGDS), which catalyses the isomerization of PGH2 to PGD2. Moreover, apoptosis by chemotherapeutics, PGD2 and 15d-PGJ2 was suppressed by the peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW-9662 or PPARγ siRNA. Finally, a COX-2-dependent apoptotic mechanism of all investigated chemotherapeutics was confirmed in human lung cancer cells (A549) as well as in another cervical carcinoma cell line (C33A). Collectively, this study suggests COX-2 induction and synthesis of L-PGDS-derived, PPARγ-activating PGs as a decisive target by which several chemotherapeutics induce apoptosis. COX-2 is therefore suspected to sensitize cancer cells to apoptotic death under certain circumstances, suggesting that COX-2 inhibition during cancer therapy could diminish its efficacy.

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Abbreviations

COX-2:

cyclooxygenase-2

5-FU:

5-fluorouracil

L-PGDS:

lipocalin-type prostaglandin D synthase

NSAID:

nonsteroidal antiinflammatory drug

PG:

prostaglandin

PPARγ:

peroxisome proliferator-activated receptor γ

siRNA:

small-interfering RNA

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Acknowledgements

This work was supported by grants from the Deutsche Krebshilfe eV (Bonn, Germany), Deutsche Forschungsgemeinschaft (SFB 539, TP BI.6) and Johannes und Frieda Marohn Stiftung (Erlangen, Germany).

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  1. Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany

    K Eichele, R Ramer & B Hinz

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  1. K Eichele
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Correspondence to B Hinz.

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Eichele, K., Ramer, R. & Hinz, B. Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells. Oncogene 27, 3032–3044 (2008). https://doi.org/10.1038/sj.onc.1210962

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