Decisive role of cyclooxygenase-2 and lipocalin-type prostaglandin D synthase in chemotherapeutics-induced apoptosis of human cervical carcinoma cells.
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-Delta(12,14) 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 PGH(2) to PGD2. Moreover, apoptosis by chemotherapeutics, PGD2 and 15d-PGJ2 was suppressed by the peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist, GW-9662 or PPARgamma 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, PPARgamma-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.
Eichele
K
K
Institute of Toxicology and Pharmacology, University of Rostock, Rostock, Germany.
Ramer
R
R
Hinz
B
B
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D054834:Lipocalins / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology; D034741:RNA, Small Interfering; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D000970:Antineoplastic Agents; D054834:Lipocalins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase