Impairment of the Antiproliferative Effect of Glucocorticosteroids by 11β-hydroxysteroid Dehydrogenase Type 2 Overexpression in MCF-7 Breast-cancer Cells

Lipka, C.; Mankertz, Joachim; Fromm, Michael; Lübbert, H.; Bühler, H.; Kühn, Werner; Ragosch, V.; Hundertmark, S.

doi:10.1055/s-2004-825724

Cited by 20 publications

(20 citation statements)

References 22 publications

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“…Expression of 11βHSD2 increases in some tumors and tumor cell lines (38)(39)(40). In MCF-7 breast cancer cells, glucocorticoid-induced inhibition of cell proliferation is attenuated by 11βHSD2 (41). The results of the present study indicate that a major mechanism for an antitumor effect of 11βHSD2 inhibition in colonic adenomas and carcinomas is the inhibition of COX-2 expression and production of COX-2-dependent PGs by increasing local concentrations of glucocorticoids, and that this COX-2 inhibition will markedly inhibit tumorigenesis.…”

Section: Figurementioning

confidence: 99%

Inhibition of 11β–hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans

Zhang¹,

Xu²,

Yao³

et al. 2009

J. Clin. Invest.

119

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Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE 2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11β-hydroxysteroid dehydrogenase type II (11βHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc +/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11βHSD2 inhibited COX-2-mediated PGE 2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11βHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11βHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.

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Section: Figurementioning

confidence: 99%

Inhibition of 11β–hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans

Zhang¹,

Xu²,

Yao³

et al. 2009

J. Clin. Invest.

119

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“…Major findings of this study are that 11βHSD2 expression is upregulated in TPA‐treated in vitro and in vivo models of NMSC, and both genetic knockdown and pharmacological inhibition of 11βHSD2 result in significantly reduced soft agar colony formation and tumorigenesis in cell and animal models respectively. Results of this study are significant because the specific role of 11βHSDs in NMSC have not been well‐studied, and many others have suggested 11βHSD2 may be a pro‐proliferative force because of its ability to inactivate glucocorticoids in a tissue‐specific manner . The role of 11βHSD2 in tumorigenesis has already been elucidated in colorectal cancer, and its inhibition has suppressed colon carcinogenesis in both mouse and human models .…”

Section: Discussionmentioning

confidence: 91%

Harnessing the gatekeepers of glucocorticoids for chemoprevention of non‐melanoma skin cancer

Mancha-Ramirez

Yang

Liang

et al. 2018

Molecular Carcinogenesis

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Despite effective surgical methods for non‐melanoma skin cancer (NMSC), patients suffer from tissue damage, scarring, or even disfigurement; thus, there is a need for chemopreventive approaches. Because of the complex interplay between glucocorticoids (GCs), inflammation, and cancer, we sought to determine the role of 11β‐hydroxysteroid dehydrogenase 1 and 2 (11βHSD1 and 2) in regulating GCs during skin cancer development and progression. 11βHSDs modulate the activation of GCs in a tissue‐specific manner and have been reported to play a role in development and progression of other types of cancer, but their role has not yet been reported in NMSC. Here, we found a significant upregulation of 11βHSD2 protein in skin cancer cells when compared to normal skin cells, suggesting a role for this enzyme in the multifactorial process of skin cancer development. In addition, inhibition of 11βHSD2 with siRNA resulted in significant reduction in colony formation in vitro. Finally, our in vivo study elucidated that inhibition of 11βHSD2 with pharmacological inhibitor, Glycyrrhetinic acid (GA) could significantly diminish tumorigenesis in a well‐studied in vivo mouse model of NMSC. Overall, these studies highlight for the first time a potential novel role for 11βHSD2 in NMSC development and may allow for new GC treatment approaches capable of avoiding deactivation by the enzyme. If 11βHSD2 can be inhibited as we have done here, or circumvented using modified GCs, this may lead to more efficacious outcomes for NMSC patients by preventing deactivation of the GC and minimizing resistance.

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“…Decreased expression/activity of an enzyme involved in degradation of glucocorticoids might in theory explain the observed effects of HDACi on increased GR activity, but this is unlikely to be the case in our experimental system because dose-response curves of dexamethasone stimulation at 24 h did not reveal a shift in the exogenous hormone concentrations required for the response (data not shown). In addition, RT-PCR amplification of the 11␤-HSD type II enzyme, which is responsible for limiting the antiproliferating activity of glucocorticoids in breast cancer cells (Lipka et al, 2004) did not reveal differences in expression in the absence or presence of HDACi (data not shown). Another potential mechanism may be effects of HDACi on the cell cycle, because most HDACi induce a block at the G 1 /S transition in different cell lines.…”

Section: Effects Of Hdac Inhibitors On Steroid Receptor Signalingmentioning

confidence: 83%

Opposite Effects of Histone Deacetylase Inhibitors on Glucocorticoid and Estrogen Signaling in Human Endometrial Ishikawa Cells

Rocha

Sánchez²,

Deschênes³

et al. 2005

Mol Pharmacol

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Histone deacetylase inhibitors (HDACi), which have emerged as a new class of anticancer agents, act by modulating expression of genes controlling apoptosis or cell proliferation. Here, we compared the effect of HDACi on transcriptional activation by estrogen or glucocorticoid receptors (ER and GR, respectively), two members of the steroid receptor family with cell growth regulatory properties. Like other transcription factors, steroid receptors modulate histone acetylation on target promoters. Using episomal reporter vectors containing minimal promoters to avoid promoter-specific effects, we observed that long-term (24-h) incubation with HDACi strongly stimulated GR-dependent but markedly repressed ER-dependent signaling in ER+/GR+ human endometrial carcinoma Ishikawa cells. These effects were reproduced on endogenous target genes and required incubation periods with HDACi substantially longer than necessary to increase global histone acetylation. Repression of estrogen signaling was due to direct inhibition of transcription from multiple ERalpha promoters and correlated with decreased histone acetylation of these promoters. In contrast, the strong HDACi stimulation of GR-dependent gene regulation was not accounted for by increased GR expression, but it was mimicked by overexpression of the histone acetyltransferase complex component transcriptional intermediary factor 2. Together, our results demonstrate striking and opposite effects of HDACi on ER and GR signaling that involve regulatory events independent of histone hyperacetylation on receptor target promoters.

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Impairment of the Antiproliferative Effect of Glucocorticosteroids by 11β-hydroxysteroid Dehydrogenase Type 2 Overexpression in MCF-7 Breast-cancer Cells

Cited by 20 publications

References 22 publications

Inhibition of 11β–hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans

Inhibition of 11β–hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans

Harnessing the gatekeepers of glucocorticoids for chemoprevention of non‐melanoma skin cancer

Opposite Effects of Histone Deacetylase Inhibitors on Glucocorticoid and Estrogen Signaling in Human Endometrial Ishikawa Cells

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