Cyclooxygenase-1 deletion enhances apoptosis but does not protect against ultraviolet light-induced tumors.
Inhibition or deletion of cyclooxygenase (COX)-2 has been demonstrated to protect against squamous cell cancer in many studies. Although much effort has focused on COX-2 inhibition, recent work indicates that COX-1 deletion may be nearly as protective. In this study, we used SKH-1 hairless mice in which COX-1 was selectively deleted to examine the role of COX-1 in photocarcinogenesis. After UV exposure, 40-60% less prostaglandin E2 was detected in COX-1-/- animals compared with wild-type (WT) controls. A 4-fold induction of keratinocyte apoptosis was observed in knockouts relative to WT animals, as documented by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and caspase-3 staining. Proliferation was not significantly different in COX-1+/+, COX-1+/-, and COX-1-/- animals. When susceptibility to UV-induced tumor formation was studied, tumor number, average tumor size, and time of tumor onset in COX-1-/- animals were identical to WT controls. Thus, enhanced apoptosis did not alter UV-induced skin carcinogenesis, suggesting other effects are key to nonsteroidal anti-inflammatory drug chemoprevention. These results contrast sharply with data obtained using the classic 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate cancer model in which a prominent protective effect of COX-1-/- is present. The lack of protection observed here confirms cancer mechanisms are distinct in UV- and tumor promotor-induced cancer models and indicates that chemoprevention strategies must specifically address cancer causes to be effective.
Departments of Dermatology, University of Rochester Medical Center, Rochester, New York 14642, USA. Alice_Pentland@urmc.rochester.edu
Alice P
AP
Pentland
Glynis
G
Scott
JoAnne
J
VanBuskirk
Carol
C
Tanck
Gina
G
LaRossa
Sabine
S
Brouxhon
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D051546:Cyclooxygenase 2; D005260:Female; D007527:Isoenzymes / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012867:Skin / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects*
D007527:Isoenzymes; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases