Cyclooxygenase-1 Deletion Enhances Apoptosis but Does Not Protect Against Ultraviolet Light-Induced Tumors

Pentland, Alice P.; Scott, Glynis; VanBuskirk, JoAnne; Tanck, Carol; LaRossa, Gina N.; Brouxhon, Sabine M.

doi:10.1158/0008-5472.can-04-1045

Cited by 33 publications

(45 citation statements)

References 28 publications

(32 reference statements)

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“…In other words, it is possible that the observed E-cadherin downregulation may be an indirect result of proliferative signals generated by epithelial cells in response to UV injury or exogenous PGE 2 . Previous studies by our group as well as others suggest that UVR can induce PGE 2 production and cell proliferation (22,25,31,32). To this end, our data show the lack of correlation between keratinocyte proliferation and E-cadherin down-regulation: In both in vitro and in vivo experimental settings, E-cadherin loss preceded temporally the induction of keratinocyte proliferation by at least 48 h after UVR, PGE 2 , or butaprost (EP2 agonist) treatments.…”

Section: Cancer Researchsupporting

confidence: 50%

“…A, SKH-1 mice were irradiated initially with 180 mJ/cm 2 of UVR, thrice weekly, increasing the exposure dose 10% each week for 15 wks. Tumor formation was followed over the subsequent 15 wks (weeks [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. At the 30-wk time point, small tumors (ST ), large tumors >2 mm (T ), and 30-wk non-tumor-bearing tissue (Chronic UV ) was excised and assessed for E-cadherin levels by Western immunoblotting.…”

Section: Resultsmentioning

confidence: 99%

“…UV irradiation. The dorsal skin of WT and EP2 À/À knockout mice was exposed to UVR in groups of two or three using a bank of four UVA Sun 340 sunlamps as described previously (22,25). Briefly, UVA Sun 340 sunlamps emit UV between 295 and 390 nm (includes both UVA and UVB wavelengths).…”

Section: Methodsmentioning

confidence: 99%

“…After sacrifice, mouse dorsal skin was snap frozen and the epidermis was curetted directly into ice-cold methanol as described previously (22,25). Thromboxane B 2 (Cayman Chemical) was added to samples for estimation of extraction efficiency and then buffered with 0.1 mol/L NaH 2 PO 4 (pH 4.0), and then individually loaded onto C-18 solid-phase extraction cartridges (Waters) preconditioned with ethanol and H 2 O at pH 4.…”

Section: For In Vitro Experiments Confluent Wt and Ep2mentioning

confidence: 99%

“…In the present study, we used the well-established SKH-1 hairless mouse photocarcinogenesis model (22,24,25) to investigate the potential mechanisms by which UVR regulates E-cadherin expression in skin keratinocytes. E-cadherin changes were studied acutely, both in vitro and in vivo, as well as chronically in vivo as irradiated epithelium developed early dysplasia, which progressed over time to become invasive SCCs.…”

Section: Cancer Researchmentioning

confidence: 99%

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Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

Brouxhon¹,

Kyrkanides

O’Banion³

et al. 2007

Cancer Research

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The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E 2 (PGE 2 ) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE 2 synthesis was enhanced. Inhibition of PGE 2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin downregulation. In contrast, addition of PGE 2 or the EP2 receptor agonist butaprost to PMK produced a dose-and timedependent decrease in E-cadherin. We also show that UV irradiation, via the PGE 2 -EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating Ecadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE 2 -EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers. [Cancer Res 2007;67(16):7654-64]

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Section: Cancer Researchsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: For In Vitro Experiments Confluent Wt and Ep2mentioning

confidence: 99%

Section: Cancer Researchmentioning

confidence: 99%

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Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

Brouxhon¹,

Kyrkanides

O’Banion³

et al. 2007

Cancer Research

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The immunomodulatory protein SV‐IV protects serum‐deprived cells against apoptosis but not against G0/G1 arrest: Possible implications for the survival of implanting embryo

Morelli

Peluso

Petillo

et al. 2007

Journal Cellular Physiology

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Serum deprivation induced in human lymphoblastoid Raji cells oxidative stress-associated apoptotic death and G0/G1 cell cycle arrest. Addition into culture medium of the immunomodulatory protein Seminal vesicle protein 4 (SV-IV) protected these cells against apoptosis but not against cycle arrest. The antiapoptotic activity was related to: (1) decrease of endocellular reactive Oxygen species (ROS) (2) increase of mRNAs encoding anti-oxidant enzymes (catalase, G6PD) and antiapoptotic proteins (survivin, cox-1, Hsp70, c-Fos); (3) decrease of mRNAs encoding proapoptotic proteins (c-myc, Bax, caspase-3, Apaf-1). The biochemical changes underlaying these effects were probably induced by a protein tyrosine kinase (PTK) activity triggered by the binding of SV-IV to its putative plasma membrane receptors. The ineffectiveness of SV-IV to abrogate the cycle arrest was accounted for by its downregulating effects on D1,3/E G1-cyclins and CdK2/4 gene expression, ppRb/pRb ratio, and intracellular ROS concentration. In conclusion, these experiments: (1) prove that SV-IV acts as a cell survival factor; (2) suggest the involvement of a PTK in SV-IV signaling; (3) point to cell cycle-linked enzyme inhibition as responsible for cycle arrest; (4) provide a model to dissect the cycle arrest and apoptosis induced by serum withdrawal; (5) imply a possible role of SV-IV in the survival of hemiallogenic implanting embryos.

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Cyclooxygenase‐2 expression is critical for chronic UV‐induced murine skin carcinogenesis

Fischer

Pavone

Mikulec

et al. 2007

Molecular Carcinogenesis

105

106

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While it has been established that both the constitutive and inducible forms of cyclooxygenase (COX-1 and COX-2, respectively) play important roles in chemical initiation-promotion protocols with phorbol ester tumor promoters, the contribution of these two enzymes to ultraviolet (UV) light-induced skin tumors has not been fully assessed. To better understand the contribution of COX-1 and COX-2 to UV carcinogenesis, we transferred the null allele for each isoform onto the SKH-1 hairless strain of mouse. Due to low viability on this background with complete knockout of COX-2, heterozygous mice were used in UV carcinogenesis experiments. While the lack of one allele of COX-1 had no effect on tumor outcome, the lack of one allele of COX-2 resulted in a 50-65% reduction in tumor multiplicity and a marked decrease in tumor size. Additionally, transgenic SKH-1 mice that overexpress COX-2 under the control of a keratin 14 promoter developed 70% more tumors than wild-type SKH-1 mice. The lack of one allele of either COX-1 or COX-2 reduced prostaglandin (PG) E2 levels in response to a single UV treatment. The proliferative response to UV was significantly reduced in COX-2, but not COX-1, heterozygous mice. UV-induced apoptosis, however, was greater in COX-2 heterozygous mice. Collectively, these results clearly establish the requirement for COX-2 in the development of skin tumors.

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Cyclooxygenase-1 Deletion Enhances Apoptosis but Does Not Protect Against Ultraviolet Light-Induced Tumors

Cited by 33 publications

References 28 publications

Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2–Dependent Posttranslational Mechanism

The immunomodulatory protein SV‐IV protects serum‐deprived cells against apoptosis but not against G0/G1 arrest: Possible implications for the survival of implanting embryo

Cyclooxygenase‐2 expression is critical for chronic UV‐induced murine skin carcinogenesis

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