Functional Glucocorticoid Receptor Modulates Pancreatic Carcinoma Growth through an Autocrine Loop

Norman, James; Franz, Michael; Schiro, Richelle; Nicosia, Santo V.; Docs, Jon; Fabri, Peter J.; Gower, William R.

doi:10.1006/jsre.1994.1105

Cited by 25 publications

(26 citation statements)

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“…Glucocorticoid action on the developing pancreas has not been extensively studied; however, previous work on the immature pancreas (Lu et al 1987, Komatsu et al 1998, poorly differentiated pancreatic cancers (Norman et al 1994) and largely exocrine pancreatic cell lines (Rosewicz et al 1991, Slater et al 1993 shows clear evidence of GR expression and that glucocorticoids reduce proliferation rate (Norman et al 1994) and alter gene expression via GR (Rosewicz et al 1991, Slater et al 1993. Indeed dexamethasone is a useful component of chemotherapy for poorly differientated pancreatic cancers (Norman et al 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed dexamethasone is a useful component of chemotherapy for poorly differientated pancreatic cancers (Norman et al 1994). Literature on the more mature pancreas indicates GR expression in islets (Matthes et al 1994) (co-localising exclusively to -cells (Fischer et al 1990)) while GR in exocrine pancreas is much reduced (Matthes et al 1994).…”

Section: Discussionmentioning

confidence: 99%

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Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development

Speirs¹,

Seckl²,

Brown³

2004

Journal of Endocrinology

130

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Glucocorticoids play important roles in organ development and 'fetal programming'. Fetal exposure to excess glucocorticoids reduces birth weight and causes later hypertension. To investigate these processes further we have determined the detailed ontogeny in the mouse of the glucocorticoid receptor (GR) and 11 -hydroxysteroid dehydrogenase type-1 (11 -HSD1), which amplifies glucocorticoid levels locally; the ontogeny was determined using in situ hybridisation from embryonic day 9·5 (E9·5, term=E19) until after birth.At E9·5 fetal GR mRNA levels are very low, except in fetal placenta. GR gene expression rises during gestation with striking tissue-specific differences in timing and extent. Before E13·5, an increase is clear in gastrointestinal (GI) and upper respiratory tracts, discrete central nervous system (CNS) regions, precartilage and especially in the liver (E10·5-E12). Later, further increases occur in lung, GI and upper respiratory tracts, muscle, pituitary and thymus. In a few tissues such increases are temporary, e.g. ureteric ducts (E13·5-E16·5) and pancreas (E14·5-E16·5, expression later falling sharply).Fetal 11 -HSD1 mRNA expression is first clearly observed at E14·5-E15, initially in the fetal placenta then in the umbilical cord. Later, 11 -HSD1 expression is seen as follows: (i) from E15 in lung and liver, rising strongly; (ii) thymus, from E15 (lower level); (iii) at low levels in a few brain regions, including the hippocampus (E16·5+); and (iv) in muscle group fascial planes and tendon insertions.This is the first detailed study of the ontogeny of these two genes and, in combination with previous work on the ontogeny of 11 -HSD2 and the mineralocorticoid receptor, suggests potential critical periods of glucocorticoid sensitivity during development for several organ systems.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development

Speirs¹,

Seckl²,

Brown³

2004

Journal of Endocrinology

130

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“…However, there are several possible explanations for the growth inhibitory effects of AhR agonists, such as that the AhR-ARNT complex may interact with other growth regulatory systems. Furthermore, it is involved in the transcriptional activation of interleukin-1b and plasminogen activator inhibitor-2 as well as in the transcriptional repression of the glucocorticoid receptor, all of which have the potential to influence cell growth (Sakai et al, 1988;Sutter et al, 1991) and have been found to be activated in PCa (Norman et al, 1994;Takeuchi et al, 1993). Additionally, an interaction between the nuclear AhR-ARNT complex and the Sp1 protein has been reported previously (Kobayashi et al, 1996;Wang et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer

et al. 2002

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The arylhydrocarbon receptor (AhR) was initially identified as a member of the adaptive metabolic and toxic response pathway to polycyclic aromatic hydrocarbons and to halogenated dibenzo-p-dioxins and dibenzofurans. In the present study, we sought to determine the functional significance of the AhR pathway in pancreatic carcinogenesis. AhR expression was analysed by Northern blotting. The exact site of AhR expression was analysed by in situ hybridization and immunohistochemistry. The effects of TCDD and four selective AhR agonists on pancreatic cancer cell lines were investigated by growth assays, apoptosis assays, and induction of the cyclin-dependent kinase inhibitor p21. There was strong AhR mRNA expression in 14 out of 15 pancreatic cancer samples, weak expression in chronic pancreatitis tissues, and faint expression in all normal pancreata. In pancreatic cancer tissues, AhR mRNA and protein expression were localized in the cytoplasm of pancreatic cancer cells. TCDD and the four AhR agonists inhibited pancreatic cancer cell growth in a dose-dependent manner, and decreased anchorage-independent cell growth. DAPI staining did not reveal nuclear fragmentation and CYP1A1 and was not induced by TCDD and AhR agonists. In contrast, TCDD and AhR agonists induced the expression of the cyclindependent kinase inhibitor p21. In conclusion, the relatively non-toxic AhR agonists caused growth inhibition in pancreatic cancer cells with high AhR expression levels via cell cycle arrest. In addition, almost all human pancreatic cancer tissues expressed this receptor at high levels, suggesting that these or related compounds may play a role in the therapy of pancreatic cancer in the future.

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“…Untreated Suit-2-SEL1L cells and DEX-treated Suit-2-pDEX.1 cells showed intermediate growth rates. The well-known antiproliferative effect of glucocorticoids on a variety of cell types both in vitro and in vivo most likely explains the difference in proliferation between treated and untreated clones (Cook et al, 1988;Thompson, 1989;Norman et al, 1994;Kudawara et al, 2001). The observed differences between untreated Suit-2-pDEX.1 and Suit-2-SEL1L cells may be explained by promoter leakage and, thus, the antiproliferative effect of increased SEL1L expression.…”

Section: Suppression Of Tumorigenicity By Sel1l In Immunodeficient Micementioning

confidence: 97%

SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo

et al. 2003

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Recent data suggest that SEL1L may play an important role in pancreatic carcinoma, similar to breast cancer, where the expression of SEL1L has been associated with a reduction in both proliferative activity in vitro and clinical tumor aggressiveness. To investigate this possibility, we examined the expression of Sel1L in a series of primary pancreatic carcinomas by immunohistochemistry and characterized the effects of Sel1L overexpression both in vitro and in vivo. In 74 pancreatic cancers analysed, 36% lacked Sel1L expression, although there was no significant correlation between the expression of Sel1L and any clinicopathologic parameter, including survival. However, immunohistochemical reactivity for Sel1L and Dpc4/ Smad4 was concordant in 69% of cases (v 2 test Po0.004). Overexpression of SEL1L in stably transfected pancreatic cancer cells caused both a decrease in clonogenicity and anchorage-independent growth as well as a significant increase in the levels of activin A and SMAD4. When implanted in nude mice, Suit-2-SEL1L-overexpressing clones displayed a considerably reduced rate of tumor growth. Thus, it can be hypothesized that Sel1L plays an important function in the growth and aggressiveness of pancreatic carcinoma. Moreover, our data provide evidence that SEL1L has an impact on the expression of genes involved in regulation of cellular growth, possibly through the TGF-b signaling pathway.

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Functional Glucocorticoid Receptor Modulates Pancreatic Carcinoma Growth through an Autocrine Loop

Cited by 25 publications

References 0 publications

Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development

Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development

Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer

SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo

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