Browsing by Author "Martel, Kellie Clay"

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    Mice lacking epidermal PPARγ exhibit a marked augmentation in photocarcinogenesis associated with increased UVB-induced apoptosis, inflammation and barrier dysfunction
    (Wiley, 2012-10) Sahu, Ravi P.; DaSilva, Sonia C.; Rashid, Badri; Martel, Kellie Clay; Jernigan, Danielle; Mehta, Shama R.; Mohamed, Deena R.; Rezania, Samin; Bradish, Joshua R.; Armstrong, Andrew B.; Warren, Simon; Konger, Raymond L.; Department of Medicine, IU School of Medicine
    Recent studies suggest that peroxisome proliferator-activated receptor gamma (PPARγ) agonists may have cancer chemopreventive activity. Other studies have shown that loss of epidermal PPARγ results in enhanced chemical carcinogenesis in mice via unknown mechanisms. However, ultraviolet B (UVB) exposure represents the primary etiological agent for skin cancer formation and the role of PPARγ in photobiology and photocarcinogenesis is unknown. In previous studies, we demonstrated that UVB irradiation of cells results in the formation of oxidized glycerophosphocholines that exhibit PPARγ ligand activity. We therefore hypothesized that PPARγ would prove to be a chemopreventive target in photocarcinogenesis. We first showed that UVB irradiation of mouse skin causes generation of PPARγ agonist species in vivo. We then generated SKH-1 hairless, albino mice deficient in epidermal Pparg (Pparg-/-(epi)) using a cytokeratin 14 driven Cre-LoxP strategy. Using a chronic model of UVB photocarcinogenesis, we next showed that Pparg-/-(epi) mice exhibit an earlier onset of tumor formation, increased tumor burden and tumor progression. Increased tumor burden in Pparg-/-(epi) mice was accompanied by a significant increase in epidermal hyperplasia and p53 positive epidermal cells in surrounding skin lacking tumors. After acute UVB irradiation, Pparg-/-(epi) mice exhibited an augmentation of both UVB-induced Caspase 3/7 activity and inflammation. Increased apoptosis and inflammation was also observed after treatment with the PPARγ antagonist GW9662. With chronic UVB irradiation, Pparg-/-(epi) mice exhibited a sustained increase in erythema and transepidermal water loss relative to wildtype littermates. This suggests that PPARγ agonists could have possible chemopreventive activity in non-melanoma skin cancer.
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    The peroxisome proliferator-activated receptor γ antagonist, GW9962, alters UVB-induced inflammatory responses, apoptosis, and delayed hyperproliferation
    (2009-01-16T17:25:58Z) Martel, Kellie Clay; Konger, Raymond L.; Travers, Jeffrey B.; Spandau, Dan F, 1957-
    It has recently been shown that the gamma subtype of the peroxisome proliferator-activated receptor (PPARγ) is a target of ultraviolet B (290-320 nm; UVB) irradiation, and that PPARγ activation is necessary for full UVB-induced cyclooxygenase-2 (COX-2) induction. However, the biological significance of PPARγ activation in cutaneous photobiology is unknown. Acute UVB irradiation results in a characteristic series of events in the epidermis which includes: an initial edema response and subsequent inflammation, COX-2 induction, apoptosis, and a delayed hyperproliferative response. Therefore, the regulatory role of PPARγ activation was examined in this acute photoresponse using a topical application of the potent, irreversible PPARγ antagonist, GW9962. GW9662 was applied to the epidermis of SKH1 hairless albino mice at increasing doses (0.01-1.0mM) prior to UVB irradiation. The photobiological responses were examined through RT-PCR, skin thickness measurements, and immunohistochemistry, at 24 and 72 hours after UVB-irradiation. At the highest dose, GW9622 significantly inhibited UVB-induced inflammation, as measured by COX-2 induction at both 24 and 72 hrs. Inflammation assessed by skin thickness measurements indicated that lower doses mildly increased inflammation at 72 hrs, but suppressed inflammation at the highest dose. In contrast, GW9662 treatment dose dependently augmented UVB-induced apoptosis at 24 hours, while affecting the delayed hyperproliferative response at 72 hours in an inverse dose-response manner. The results from this study suggest that PPARγ is a key regulator of these photobiological responses. Because these responses are well known to be involved in tumor development and progression, this study also suggests a potential role for PPARγ in UVB-induced skin cancers.