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Cyclooxygenase-1 deletion enhances apoptosis but does not protect against ultraviolet light-induced tumors
Alice P Pentland1, Glynis Scott, JoAnne VanBuskirk
1Departments of Dermatology, University of Rochester Medical Center, Rochester, New York 14642, USA. Alice_Pentland@urmc.rochester.edu
Abstract:
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.
Insights
Selective deletion of cyclooxygenase-1 (COX-1) did not protect against UV-induced skin cancer in mice, despite increasing apoptosis. This suggests COX-1 is not a key target for photocarcinogenesis chemoprevention.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Cyclooxygenase-2 (COX-2) inhibition is studied for squamous cell cancer prevention.
- Recent research suggests cyclooxygenase-1 (COX-1) deletion may also offer protection.
- The role of COX-1 in UV-induced skin carcinogenesis requires further investigation.
Purpose of the Study:
- To investigate the role of COX-1 in photocarcinogenesis using COX-1 deleted mice.
- To determine if COX-1 deletion influences UV-induced skin tumor development.
- To compare the effects of COX-1 deletion in UV-induced versus chemical carcinogen-induced cancer models.
Main Methods:
- Utilized SKH-1 hairless mice with selective COX-1 deletion (COX-1-/-).
- Administered UV exposure to induce photocarcinogenesis.
- Quantified prostaglandin E2 levels, keratinocyte apoptosis (TUNEL, caspase-3), and cell proliferation.
- Assessed tumor formation, size, and onset time.
Main Results:
- COX-1-/- mice showed 40-60% less prostaglandin E2 and a 4-fold increase in keratinocyte apoptosis compared to wild-type (WT) controls.
- No significant differences in proliferation were observed across genotypes (COX-1+/+, COX-1+/-, COX-1-/-).
- Tumor number, size, and onset were identical in COX-1-/- and WT mice following UV exposure, contrasting with protection seen in a chemical carcinogen model.
Conclusions:
- Enhanced apoptosis in COX-1-/- mice did not prevent UV-induced skin carcinogenesis.
- COX-1 is not a critical factor in UV-induced skin cancer development.
- Cancer mechanisms differ between UV- and chemical carcinogen-induced models, necessitating targeted chemoprevention strategies.
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