Browsing by Author "Kemp, Michael G."

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Creatine and Nicotinamide Prevent Oxidant-Induced Senescence in Human Fibroblasts
    (MDPI, 2021-11-16) Mahajan, Avinash S.; Arikatla, Venkata S.; Thyagarajan, Anita; Zhelay, Tetyana; Sahu, Ravi P.; Kemp, Michael G.; Spandau, Dan F.; Travers, Jeffrey B.; Dermatology, School of Medicine
    Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer. The present studies tested the hypothesis that pro-energetics creatine monohydrate (Cr) and nicotinamide (NAM) can protect normal dermal human fibroblasts (DHF) against experimentally induced senescence. To that end, we used an experimental model of senescence in which primary DHF are treated with hydrogen peroxide (H2O2) in vitro, with senescence measured by staining for beta-galactosidase activity, p21 protein expression, and senescence associated secretory phenotype cytokine mRNA levels. We also determined the effect of H2O2 on IGF-1 mRNA and protein expression. Our studies indicate that pretreatment with Cr or NAM protects DHF from the H2O2-induced cell senescence. Treatment with pro-energetics post-H2O2 had no effect. Moreover, these agents also inhibited reactive oxygen species generation from H2O2 treatment. These studies suggest a potential strategy for protecting fibroblasts in geriatric skin from undergoing stress-induced senescence, which may maintain IGF-1 levels and therefore limit carcinogenesis in epidermal keratinocytes.
  • Thumbnail Image
    Item
    Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin
    (MDPI, 2017-02-26) Kemp, Michael G.; Spandau, Dan F.; Travers, Jeffrey B.; Dermatology, School of Medicine
    The growing incidence of non-melanoma skin cancer (NMSC) necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV) wavelengths of sunlight and age. Whereas UV radiation (UVR) has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1) by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC.
  • Thumbnail Image
    Item
    Insulin-like Growth Factor 1 Receptor Signaling Is Required for Optimal ATR-CHK1 Kinase Signaling in Ultraviolet B (UVB)-irradiated Human Keratinocytes
    (American Society for Biochemistry and Molecular Biology, 2017-01-27) Kemp, Michael G.; Spandau, Dan F.; Simman, Richard; Travers, Jeffrey B.; Biochemistry and Molecular Biology, School of Medicine
    UVB wavelengths of light induce the formation of photoproducts in DNA that are potentially mutagenic if not properly removed by the nucleotide excision repair machinery. As an additional mechanism to minimize the risk of mutagenesis, UVB-irradiated cells also activate a checkpoint signaling cascade mediated by the ATM and Rad3-related (ATR) and checkpoint kinase 1 (CHK1) kinases to transiently suppress DNA synthesis and cell cycle progression. Given that keratinocytes in geriatric skin display reduced activation of the insulin-like growth factor 1 receptor (IGF-1R) and alterations in DNA repair rate, apoptosis, and senescence following UVB exposure, here we used cultured human keratinocytes in vitro and skin explants ex vivo to examine how IGF-1R activation status affects ATR-CHK1 kinase signaling and the inhibition of DNA replication following UVB irradiation. We find that disruption of IGF-1R signaling with small-molecule inhibitors or IGF-1 withdrawal partially abrogates both the phosphorylation and activation of CHK1 by ATR and the accompanying inhibition of chromosomal DNA synthesis in UVB-irradiated keratinocytes. A critical protein factor that mediates both ATR-CHK1 signaling and nucleotide excision repair is replication protein A, and we find that its accumulation on UVB-damaged chromatin is partially attenuated in cells with an inactive IGF-1R. These results indicate that mutagenesis and skin carcinogenesis in IGF-1-deficient geriatric skin may be caused by defects in multiple cellular responses to UVB-induced DNA damage, including through a failure to properly suppress DNA synthesis on UVB-damaged DNA templates.
  • Thumbnail Image
    Item
    Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia
    (The American Society for Clinical Investigation, 2021) Spandau, Dan F.; Chen, Roy; Wargo, Jeffrey J.; Rohan, Craig A.; Southern, David; Zhang, Angela; Loesch, Mathew; Weyerbacher, Jonathan; Tholpady, Sunil S.; Lewis, Davina A.; Kuhar, Matthew; Tsai, Kenneth Y.; Castellanos, Amber J.; Kemp, Michael G.; Markey, Michael; Cates, Elizabeth; Williams, Amy R.; Knisely, Christina; Bashir, Sabina; Gabbard, Ryan; Hoopes, Robert; Travers, Jeffrey B.; Biochemistry and Molecular Biology, School of Medicine
    BACKGROUND: The loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC. METHODS: A human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion. RESULTS: Xenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs). CONCLUSION: The elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.
  • Thumbnail Image
    Item
    Wounding Therapies for Prevention of Photocarcinogenesis
    (Frontiers Media, 2022-01-07) Frommeyer, Timothy C.; Rohan, Craig A.; Spandau, Dan F.; Kemp, Michael G.; Wanner, Molly A.; Tanzi, Elizabeth; Travers, Jeffrey B.; Dermatology, School of Medicine
    The occurrence of non-melanoma skin cancer (NMSC) is closely linked with advanced age and ultraviolet-B (UVB) exposure. More specifically, the development of NMSC is linked to diminished insulin-like growth factor-1 (IGF-1) signaling from senescent dermal fibroblasts in geriatric skin. Consequently, keratinocyte IGF-1 receptor (IGF-1R) remains inactive, resulting in failure to induce appropriate protective responses including DNA repair and cell cycle checkpoint signaling. This allows UVB-induced DNA damage to proliferate unchecked, which increases the likelihood of malignant transformation. NMSC is estimated to occur in 3.3 million individuals annually. The rising incidence results in increased morbidity and significant healthcare costs, which necessitate identification of effective treatment modalities. In this review, we highlight the pathogenesis of NMSC and discuss the potential of novel preventative therapies. In particular, wounding therapies such as dermabrasion, microneedling, chemical peeling, and fractionated laser resurfacing have been shown to restore IGF-1/IGF-1R signaling in geriatric skin and suppress the propagation of UVB-damaged keratinocytes. This wounding response effectively rejuvenates geriatric skin and decreases the incidence of age-associated NMSC.
  • Thumbnail Image
    Item
    Wounding with a Microneedling Device Corrects the Inappropriate Ultraviolet B Radiation Response in Geriatric Ski
    (SpringerLink, 2020-01) Travers, Jeffrey B.; Kemp, Michael G.; Weir, Nathan M.; Cates, Elizabeth; Alkawar, Abdulrahman M.; Mahajan, Avinash S.; Spandau, Dan F.; Dermatology, School of Medicine
    Non-melanoma skin cancer primarily affects geriatric patients as evidenced by the fact that only 20% of these cancers are diagnosed in patients under the age of 60 years. Of importance, geriatric skin responds to procarcinogenic ultraviolet B radiation (UVB) in a manner that permits the establishment of tumor cells. Recent studies have indicated that wounding of geriatric skin with fractionated resurfacing lasers and dermabrasion upregulates fibroblast production of insulin-like growth factor-1 (IGF-1) and normalizes the procarcinogenic acute UVB response consisting of basal keratinocytes proliferating while still harboring unrepaired DNA damage. The present studies tested the ability of wounding with a commercially available microneedling device to upregulate IGF-1 levels and normalize the geriatric UVB response. Geriatric volunteers were treated with a microneedling device on buttock skin and 3 months later the IGF-1 levels and UVB responses tested in wounded vs control skin. Wounding via microneedling upregulated IGF-1 and resulted in lower levels of basal keratinocytes proliferating with unrepaired DNA damage. The ability of microneedling to protect against the formation of UVB-damaged proliferating keratinocytes indicates the potential of this wounding modality to reduce aging-associated non-melanoma skin cancer.