Loss of glucocorticoid-dependent growth inhibition in transformed mouse lung cells

Li, Jia; Johnson, Todd A.; Hanson, Laurie A.; Beer, David G.

doi:10.1002/(sici)1098-2744(199608)16:4<213::aid-mc5>3.0.co;2-g

Cited by 10 publications

(1 citation statement)

References 33 publications

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“…However, glucocorticoids usage is limited due to their numerous side effects [36, 37]. Glucocorticoids also do not affect the growth of either established papillomas, squamous cell carcinomas (SCC), or transformed keratinocytes in vitro; skin papillomas and carcinomas become resistant to the growth inhibition by glucocorticoids and their control of cellular functions [6, 38, 39].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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Resistance of transformed mouse keratinocytes to growth inhibition by glucocorticoids

Spiegelman¹,

Budunova²,

Carbajal³

et al. 1997

Mol. Carcinog.

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Glucocorticoid hormones are strong inhibitors of normal keratinocyte proliferation, but established mouse skin papillomas and carcinomas become resistant to these hormones. The biological effect of glucocorticoids is mediated through a highly specific glucocorticoid receptor (GR). To study the possible mechanisms of glucocorticoid resistance of transformed mouse keratinocytes, we evaluated GR expression and function in non-tumorigenic (3PC), papilloma-producing (MT1/2 and P1/17), and squamous cell carcinoma-producing (Ca3/7 and Ca8/29) keratinocyte cell lines and analyzed the DNA sequence of GR in glucocorticoid-sensitive and glucocorticoid-resistant keratinocytes. All transformed keratinocyte cell lines studied appeared to be completely resistant to the growth inhibition by the glucocorticoid fluocinolone acetonide (FA), whereas the untransformed cell line 3PC was very sensitive to FA. Despite the glucocorticoid resistance, all the tumorigenic keratinocyte cell lines expressed high levels of GR mRNA and protein. Southern blot analysis and direct sequencing of the DNA-binding domain of the GR gene revealed no significant changes in GR gene structure in transformed keratinocytes. To test the functional capability of GR, we compared the effect of FA on the expression of glucocorticoid-responsive genes. FA strongly induced metallothionein 1 expression in 3PC cells, slightly induced metallothionein 1 expression in P1/17 and Ca3/7 cells, and did not affect its expression in MT1/2 and Ca8/29 cells. These data suggest that resistance to the growth inhibition of glucocorticoids is an important feature of tumorigenic keratinocyte cell lines. It is likely that this hormone-resistant phenotype is a result of alteration of GR function but not of GR expression or gene structure.

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The Non-Conventional Effects of Glucocorticoids in Cancer

et al. 2016

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Synthetic corticosteroids are widely used for the treatment of a variety of diseases, including pre-malignant and malignant conditions. In striking contrast, recent evidence suggests that corticosteroids can bear tumor-promoting effects in solid tumors of epithelial origin. We have recently shown that epithelial tissues, including the mucosa of the oral cavity and the skin, are able to modulate the local concentration of active corticosteroids and to produce steroids de novo. This has important clinical and physiopathological implications, because tissue-specific regulation of glucocorticoids plays a key role in the overall effect of these molecules. In the present review of the current English literature, performed using MEDLINE/PubMed/Ovid databases, we collected published evidence to demonstrate that corticosteroids induce effects that are more complex and controversial than previously acknowledged. Published studies clearly demonstrate that this class of molecules influences pathophysiological processes that are strictly related to malignancy, providing the rationale for further investigation. J. Cell. Physiol. 231: 2368-2373, 2016. © 2016 Wiley Periodicals, Inc.

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Loss of glucocorticoid-dependent growth inhibition in transformed mouse lung cells

Cited by 10 publications

References 33 publications

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

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

Resistance of transformed mouse keratinocytes to growth inhibition by glucocorticoids

The Non-Conventional Effects of Glucocorticoids in Cancer

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