Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

Thomas, Jeffrey; Liu, Tong; Cotter, Murray A.; Florell, Scott R.; Robinette, Kyle; Hanks, Adrianne N.; Grossman, Douglas

doi:10.1158/0008-5472.can-06-3669

Cited by 38 publications

(41 citation statements)

References 45 publications

(60 reference statements)

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“…its targeted expression in skin predispose mice to UV-induced tumors. 36 Our studies show that, mutant K-Ras also depends on survivin for its ability to transform cells as well as to induce invasion. Using a genetically defined pancreatic cancer cell model (HPNE), we have shown that the ability of mutant K-Ras to induce anchorage-independent cell growth on soft agar was inhibited by depletion of survivin.…”

Section: Discussionmentioning

confidence: 62%

Depletion of K-Ras promotes proteasome degradation of survivin

Tecleab

Sebti²

2013

Cell Cycle

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Section: Discussionmentioning

confidence: 62%

Depletion of K-Ras promotes proteasome degradation of survivin

Tecleab

Sebti²

2013

Cell Cycle

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“…In this study, we conducted a trial of orally administered NAC in a highly penetrant mouse model of melanoma (20), in which animals develop tumors following a single UV exposure in the neonatal period. Additionally, we characterized the generation of oxidative stress/damage following UV irradiation of a mouse melanocyte cell line and mouse skin.…”

mentioning

confidence: 99%

N-Acetylcysteine Protects Melanocytes against Oxidative Stress/Damage and Delays Onset of Ultraviolet-Induced Melanoma in Mice

Cotter

Thomas

Cassidy

et al. 2007

Clinical Cancer Research

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Purpose: UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies.We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UVinduced oxidative stress/damage in vitro and from UV-induced melanoma in vivo. Experimental Design: In vitro experiments used the mouse melanocyte line melan-a. For in vivo experiments, mice transgenic for hepatocyte growth factor and survivin, shown previously to develop melanoma following a single neonatal dose of UV irradiation, were given NAC (7 mg/mL; mother's drinking water) transplacentally and through nursing until 2 weeks after birth. Results: NAC (1-10 mmol/L) protected melan-a cells from several UV-induced oxidative sequelae, including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine, and depletion of free reduced thiols (primarily glutathione). Delivery of NAC reduced thiol depletion and blocked formation of 8-oxoguanine in mouse skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared with control mice (21versus 14 weeks; P = 0.0003). Conclusions: Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma and suggest that NAC may be useful as a chemopreventive agent.

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“…15. After antigen retrieval performed as described above, sections were blocked with 5% BSA for 45 min, subjected to the TUNEL assay, washed three times with PBS, and stained for γ ‐H2AX as described above.…”

Section: D Tissues and Anticancer Drugsmentioning

confidence: 99%

Evaluation of surrogate tissues as indicators of drug activity in a melanoma skin model

et al. 2016

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The development of novel cancer treatments is a challenging task, partly because results from model systems often fail to predict drug efficacy in humans, and also tumors are often inaccessible for biochemical analysis, preventing effective monitoring of drug activity in vivo. Utilizing a model system, we evaluated the use of drug‐induced DNA damage in surrogate tissues as indicators of drug efficacy. Samples of a commercially available melanoma skin model (Mattek MLNM‐FT‐A375) containing keratinocyte and fibroblast layers with melanoma nodules were subjected to various chemotherapeutic regimens for one, four, or eight days. At these times they were analyzed for DNA double‐stranded breaks (γH2AX foci) and apoptosis (TUNEL). A wide range of drug responses in both tumor and normal tissues were observed and cataloged. For the melanoma, the most common drug response was apoptosis. The basal keratinocyte layer, which was the most reliable indicator of drug response in the melanoma skin model, responded with γH2AX foci formation that was abrupt and transient. The relationships between tumor and surrogate tissue drug responses are complex, indicating that while surrogate tissue drug responses may be useful clinical tools, careful control of variables such as the timing of sampling may be important in interpreting the results.

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Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

Cited by 38 publications

References 45 publications

Depletion of K-Ras promotes proteasome degradation of survivin

Depletion of K-Ras promotes proteasome degradation of survivin

N-Acetylcysteine Protects Melanocytes against Oxidative Stress/Damage and Delays Onset of Ultraviolet-Induced Melanoma in Mice

Evaluation of surrogate tissues as indicators of drug activity in a melanoma skin model

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