Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis

Budunova, Irina; Carbajal, Steve; Kang, Ho Il; Viaje, Aurora; Slaga, Thomas J.

doi:10.1002/(sici)1098-2744(199703)18:3<177::aid-mc7>3.0.co;2-c

Cited by 34 publications

(21 citation statements)

References 28 publications

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“…It was established initially that Ca3/7 and Mt1/2 cells (but not 3PC cells) were completely resistant to growth inhibition by 0.001–100 µM of FA, which is in agreement with our previous data 25, 26. Because DMI enhanced the GC‐induced GR‐mediated transcription in previous studies, we examined the combination effect on growth inhibitions in the Ca3/7 cell line.…”

Section: Resultssupporting

confidence: 89%

“…Some human tumors and murine skin tumor cell lines were shown to be resistant to GC‐mediated growth inhibition 21–24. Moreover, analysis of GR expression in mouse skin tumors revealed that GR mRNA and protein levels in most tumors are similar to or higher than those in normal mouse epidermis 25. To study the possible mechanisms of GC resistance of transformed mouse keratinocytes, we evaluated GR function in nontumorigenic (3PC), papilloma‐producing (MT1/2), and squamous cell carcinoma‐producing (Ca3/7) keratinocyte cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor‐mediated transcription

Kinjo

Kowalczyk

et al. 2009

Molecular Carcinogenesis

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The purpose of this study was to examine the effect of tricyclic antidepressant desipramine (DMI) on the growth inhibition and translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus in cancerous and noncancerous cell lines and the effect of DMI on GR-mediated transcription. Nontumorigenic, immortalized keratinocytes cell line (3PC), papilloma (MT1/2), and squamous cell carcinoma (Ca3/7) cell lines were initially used to study the cell growth inhibition by DMI. Although, the growth of all three cell lines was suppressed by DMI, it was more effective in Ca3/7 cells. Therefore, we next examined the effect of DMI on Ca3/7 cells, resistant to growth inhibition by the synthetic glucocorticoid fluocinolone acetonide (FA). DMI inhibited cell proliferation in a time-dependent manner. The translocation of GR was induced by FA alone, DMI alone, and combination of both agents. FA induced GR-mediated transcription in Ca3/7 cells transfected with a luciferase reporter gene under the control of glucocorticoid response element (GRE), but DMI alone did not affect GR-mediated transcription. However, DMI inhibited FA-induced, GR-mediated transcription when both agents were given together. Pretreatment with DMI followed by combination of DMI and FA decreased GR-mediated transcription more than pretreatment with FA. The expression of metallothionein-1 (Mt-1) gene, which is regulated by GR, was induced significantly by the combination of DMI and FA, and enhanced significantly by pretreatment with FA but not DMI. DMI is suggested to inhibit the growth of Ca3/7 cells and to affect GR-mediated transcription.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor‐mediated transcription

Kinjo

Kowalczyk

et al. 2009

Molecular Carcinogenesis

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“…Experiments with transgenic mice harboring mutated GR, which cannot activate GRE containing promoters, clearly indicate that many important effects of glucocorticoids, including their anti‐inflammatory effect and blockage of tumor promoter 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced response in skin, depend on GR's transrepressive effects on NF‐κB and AP‐1 [4]. However, skin papillomas and carcinomas become resistant to growth inhibition by glucocorticoids and their control of cellular functions [5–7]. Both, AP‐1 and NF‐κB activities are significantly elevated in mouse skin tumors and appear to be related to the loss of the GR function [8–10].…”

Section: Introductionmentioning

confidence: 99%

The possible separation of 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced skin inflammation and hyperplasia by compound A

Kowalczyk

Junco

et al. 2012

Molecular Carcinogenesis

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Activated glucocorticoid receptor (GR) acts via two different mechanisms: transcriptional regulation that requires DNA-binding, and protein–protein interaction between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1). It has been postulated that many important effects of glucocorticoids, including their anti-inflammatory properties, depend on GR’s transrepressive effects on NF-κB and AP-1. In the present study, we have employed a TPA-induced model of skin inflammation and epidermal hyperplasia to determine whether partial activation of the glucocorticoid receptor by Compound A (CpdA) is sufficient to reverse the effect of TPA treatment. CpdA is a nonsteroidal GR modulator with high binding affinity, is capable of partial activation of GR. Topical application of TPA twice per week for two weeks results in inflammation and epidermal hyperplasia. TPA treatment also elevates levels of c-jun (AP-1 component), cyclooxygenase-2 (COX-2), p50 (NF-κB component), interleukin-6 (IL-6) and tumor necrosis factor (TNF) in the skin. Fluocinolone acetonide (FA) (a full GR agonist) was able to completely reverse the above effects of TPA. When applied alone, CpdA increased the epidermal thickness and keratinocyte proliferation as well as levels of c jun, COX-2, IL-6 and IFN-γ. However CpdA treatment resulted in a decrease in the number of p50 positive cells induced by TPA, suggesting its role in inhibition of NF-κB. The level of metallothionein-1 mRNA, regulated by GR was also significantly decreased in skin samples treated with CpdA. Our results suggest that CpdA is able to inhibit GR transactivation and activate only some transrepression properties of GR.

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“…Skin was harvested and epidermis was mechanically isolated from dermis by scraping as described. 36 Total RNA was isolated from cells or epidermis by Tri-Reagent (Sigma-Aldrich) according to the manufacturer’s protocol. The gene expression levels were assessed in samples of epidermis from individual animals (3–4 animals/group) using two-step reverse transcription-PCR.…”

Section: Methodsmentioning

confidence: 99%

“…with bromodeoxyuridine (BrdU; Sigma-Aldrich; 50 μg/g of animal weight) 1 hour before skin was harvested as in. 36 …”

Section: Methodsmentioning

confidence: 99%

Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

et al. 2015

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Background:Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcription factor that causes either gene transactivation (TA) or transrepression (TR). Compound A (CpdA), a novel non-steroidal GR ligand, does not promote GR dimerization and TA, retains anti-inflammatory potential but induces fewer metabolic side effects compared to classical glucocorticoids when used systemically. As topical effects of CpdA have not been well studied, this work goal was to compare the anti-inflammatory and side effects of topical CpdA and glucocorticoids and to assess their effect on GR TA and TR in keratinocytes.Methods:We used murine immortalized keratinocytes and F1 C57BlxDBA mice. Effect of glucocorticoid fluocinolone acetonide (FA) and CpdA on gene expression in keratinocytes in vitro and in vivo was evaluated by reverse transcription-PCR. The anti-inflammatory effects were assessed in the model of tumor promoter 12-O-tertradecanoyl-acetate (TPA)-induced dermatitis and in croton oil-induced ear edema test. Skin atrophy was assessed by analysis of epidermal thickness, keratinocyte proliferation, subcutaneous adipose hypoplasia, and dermal changes after chronic treatment with FA and CpdA.Results:In mouse keratinocytes in vitro and in vivo, CpdA did not activate GR-dependent genes but mimicked closely the inhibitory effect of glucocorticoid FA on the expression of inflammatory cytokines and matrix metalloproteinases. When applied topically, CpdA inhibited TPA-induced skin inflammation and hyperplasia. Unlike glucocorticoids, CpdA itself did not induce skin atrophy which correlated with lack of induction of atrophogene regulated in development and DNA damage response 1 (REDD1) causatively involved in skin and muscle steroid-induced atrophy.Conclusions:Overall, our results suggest that CpdA and its derivatives represent novel promising class of anti-inflammatory compounds with reduced topical side effects.

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Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis

Cited by 34 publications

References 28 publications

Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor‐mediated transcription

Desipramine inhibits the growth of a mouse skin squamous cell carcinoma cell line and affects glucocorticoid receptor‐mediated transcription

The possible separation of 12‐O‐tetradecanoylphorbol‐13‐acetate‐induced skin inflammation and hyperplasia by compound A

Selective Activator of the Glucocorticoid Receptor Compound A Dissociates Therapeutic and Atrophogenic Effects of Glucocorticoid Receptor Signaling in Skin

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