Activation of the insulin-like growth factor-1 receptor promotes the survival of human keratinocytes following ultraviolet B irradiation

Abstract

The ultraviolet B (UVB) component of sunlight causes non‐melanoma skin cancers due to the damage it inflicts on genomic DNA. The response of epidermal keratinocytes to sunlight depends on the dose of UVB received and the severity of the damage to the DNA. Mild DNA damage typically induces DNA‐repair pathways and cell survival, while severe DNA damage provokes apoptosis. Primary human keratinocytes grown in serum‐free media respond in a similar manner to UVB irradiation. However, we observed that keratinocytes are exquisitely more susceptible to UVB‐induced apoptosis if the growth medium is depleted of exogenous growth factors. Therefore, an exogenous growth factor could provide protection from UVB‐induced apoptosis. We found that the only growth factor that provided protection from UVB‐induced apoptosis was insulin and that the protective effect elicited by insulin was not due to binding the insulin receptor but, rather, to activation of the insulin‐like growth factor‐1 (IGF‐1) receptor. Additionally, activation of the IGF‐1 receptor in combination with UVB irradiation induced keratinocytes to become post‐mitotic. This survival function of the IGF‐1 receptor in response to UVB irradiation was influenced by activation of phosphatidylinositol‐3 kinase and MAP kinase. Prior to UVB irradiation, insulin or IGF‐1 had little to no effect on cell growth or viability. Therefore, activation of the IGF‐1 receptor in conjunction with UVB irradiation promotes keratinocyte survival at the expense of cell proliferation. Int. J. Cancer 80:431–438, 1999. © 1999 Wiley‐Liss, Inc.

Effect of type 1 insulin-like growth factor receptor targeted therapy on chemotherapy in human cancer and the mechanisms involved

“…It also oVers escape mechanisms that allow the tumor to evade conventional treatment (Samani et al 2007). Studies propose that the IGF-1R may also play a role in protection of tumor cells from DNAdamaging agents such as chemotherapy, and ionizing radiation (Gil-Ad et al 1999;Gooch et al 1999;Jiang et al 1999;Kuhn et al 1999;Liu et al 1998b;Peters et al 1996). The beneWts of IGF-1R blockade in combination with radiotherapy have been widely documented (Criswell et al 2005), however, the focus of this review is the eVect of blocking IGF-1R on chemotherapy.…”

UVB-induced Senescence in Human Keratinocytes Requires a Functional Insulin-like Growth Factor-1 Receptor and p53

“…Normal human keratinocytes were isolated from neonatal foreskin tissue (Kuhn et al, 1999). Isolated keratinocytes were grown in EpiLife Complete media (Cascade Biologics, Portland, OR) supplemented with human keratinocyte growth supplement (Cascade Biologics) and 1000 U of penicillin-streptomycin (Roche Molecular Biochemicals, Indianapolis, IN).…”

“…Fortunately, keratinocytes have developed many specific mechanisms to handle the unrelenting bombardment of carcinogenic insults. The in vitro-cultured keratinocyte model system has provided us with a wealth of information regarding how keratinocytes respond to UVB irradiation (Cotton and Spandau, 1997;Kumar et al, 1999;Kuhn et al, 1999;Qin et al, 2002;Zhang et al, 2002;Lewis et al, 2003Lewis et al, , 2006Chaturvedi et al, 2004;Lewis and Spandau, 2007a,b). In addition to the severity of UVB-induced DNA damage, events at the cell membrane of the keratinocyte, and their subsequent signal transduction cascades, critically control the fate of UVB-irradiated keratinocytes.…”

“…In addition to the severity of UVB-induced DNA damage, events at the cell membrane of the keratinocyte, and their subsequent signal transduction cascades, critically control the fate of UVB-irradiated keratinocytes. We have examined one of these cell surface events, the activation of the insulin-like growth factor-1 receptor (IGF-1R; Kuhn et al, 1999;Lewis and Spandau, 2007b), and we described three key features affecting the cellular outcome of UVB-irradiated human keratinocytes: 1) ligand-activation of the IGF-1R promotes protection from UVB-induced apoptosis; 2) although UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication; and 3) in the absence of IGF-1R activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate (Kuhn et al, 1999). We hypothesize that the first two observations were part of the normal protective response of human skin to UVB exposure, i.e., maintaining the integrity of the protective barrier function of the epidermis while ensuring that UVB-damaged keratinocytes are not permitted to replicate DNA mutations.…”

Full-thickness tissue engineered skin constructed with autogenic bone marrow mesenchymal stem cells

“…Previous research found that UVB irradiation could give rise to cell apoptosis [8][9][10] , but it could also promote human epidermal cell growth under low dose irradiation and EGF existence [11] . The induced epidermal cells could resist UVB irradiation possibly because these cells received anti-apoptosis signals such as low dose irradiation promoted Rho B expression, EGF receptor activation induced AKT signal pathway which thereby promoted BAD phosphorylation and P53 downregulation [11][12][13] . Preliminary evidence in this study indicates that the induced epidermal cells acquired normal epidermal cell function to some extent.…”