Proliferation of the murine corticotropic tumour cell line AtT20 is affected by hypophysiotrophic hormones, growth factors and glucocorticoids

Wijk, P. A. Van; Neck, Johan W. van; Rijnberk, A.; Croughs, R. J. M.; Mol, Jan A.

doi:10.1016/0303-7207(95)03541-e

Cited by 43 publications

(27 citation statements)

References 36 publications

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“…The hypophysiotropic hormone CRH (Florio et al 2007) has been previously demonstrated to significantly stimulate AtT20/D16v cell proliferation (van Wijk et al 1995). Our results show that CRH induces cell viability only in the short term, suggesting a protective rather than a proliferative effect of this peptide on corticotroph cells.…”

Section: Discussionsupporting

confidence: 50%

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

Gentilin¹,

Tagliati²,

Terzolo³

et al. 2013

Journal of Endocrinology

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Medical therapy for Cushing's disease (CD) is currently based on agents mainly targeting adrenocortical function. Lately, pituitary-directed drugs have been developed, with limited efficacy. Mitotane, a potent adrenolytic drug, has been recently investigated for the treatment of CD, but the direct pituitary effects have not been clarified so far. The aim of our study was to investigate whether mitotane may affect corticotroph function and cell survival in the mouse pituitary cell line AtT20/D16v-F2 and in the primary cultures of human ACTHsecreting pituitary adenomas, as an in vitro model of pituitary corticotrophs. We found that in the AtT20/D16v-F2 cell line and in primary cultures, mitotane reduces cell viability by inducing caspase-mediated apoptosis and reduces ACTH secretion. In the AtT20/D16v-F2 cell line, mitotane reduces Pomc expression and blocks the stimulatory effects of corticotropinreleasing hormone on cell viability, ACTH secretion, and Pomc expression. These effects were apparent at mitotane doses greater than those usually necessary for reducing cortisol secretion in Cushing's syndrome, but still in the therapeutic window for adrenocortical carcinoma treatment. In conclusion, our results demonstrate that mitotane affects cell viability and function of human and mouse ACTH-secreting pituitary adenoma cells. These data indicate that mitotane could have direct pituitary effects on corticotroph cells.

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Section: Discussionsupporting

confidence: 50%

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

Gentilin¹,

Tagliati²,

Terzolo³

et al. 2013

Journal of Endocrinology

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“…The idea that the unknown factor may be a growth factor is supported by results from our study with AtT20 cells. Proliferation of murine corticotrophic tumour cells (AtT20) induced by growth factors is, in comparison with hypothalamic neurohormones, relatively insensitive to inhibition by glucocorticoids (26). The FCS-induced proliferation of canine corticotrophic tumour cells is not sensitive to inhibition by glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

“…Because the amount of cells harvested was not suf®cient to test a great variety of growth factors, we decided, on the basis of our study with AtT20 cells (26), to test CRH, AVP and IGF-I alone and in combination with cortisol. As none of these peptides mimic the FCSinduced proliferation, further investigations are needed to elucidate the stimulating factor present in FCS.…”

Section: Discussionmentioning

confidence: 99%

“…We have shown stimulating effects of CRH, AVP, basic ®broblast growth factor, epidermal growth factor and IGF-I on the proliferation of a murine corticotrophic tumour cell line (AtT20) (26). The growth factor-induced proliferation of AtT20 cells appeared to be less sensitive to inhibition by glucocorticoids than the proliferation induced by hypothalamic hormones, and the IGF-I-induced proliferation was the least sensitive to inhibition by cortisol (26).…”

Section: Introductionmentioning

confidence: 97%

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Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro

Wijk

Rijnberk²,

Croughs³

et al. 1998

European Journal of Endocrinology

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Extrinsic factors such as hypothalamic hormones or intrapituitary growth factors may stimulate clonal expansion of a genomically altered cell and therefore play a role in pituitary tumorigenesis. Here we report on the effects of the hypophysiotrophic hormones corticotrophin-releasing hormone (CRH) and vasopressin (AVP) and the intrapituitary growth factor insulin-like growth factor-I (IGF-I) on the proliferation of, as measured by the bromodeoxyuridine labelling index, and ACTH secretion by normal canine pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism. The sensitivity to inhibition by cortisol was analysed under various conditions.Under basal conditions, no signi®cant differences were found in the bromodeoxyuridine labelling indices between control cells and tumour cells. CRH, AVP, IGF-I and cortisol had no effect on the proliferation of canine pituitary cells or canine corticotrophic adenoma cells. In contrast with normal pituitary cells, the proliferation of corticotrophic adenoma cells was stimulated by fetal calf serum (FCS). This FCS-induced proliferation was not inhibited by cortisol.The CRH-induced ACTH secretion by corticotrophic adenoma cells was signi®cantly (P < 0.05) lower than that by normal pituitary cells after 4 h incubation with CRH. Incubation with cortisol for 24 h resulted in reduced ACTH secretion under basal and AVP-or IGF-I-stimulated conditions. The relative inhibition was, however, signi®cantly (P < 0.05) lower in ACTH-producing tumour cells than in normal pituitary cells. Cortisol did not inhibit the CRH-induced ACTH secretion in normal pituitary cells after 24 h.In conclusion, canine corticotrophic adenomas are less sensitive to stimulation by CRH and less sensitive to inhibition by glucocorticoids. These tumours have an aberrant sensitivity to a growthpromoting factor present in FCS. This factor may have an important role in the growth promotion of canine corticotrophic tumours. European Journal of Endocrinology 138 309±315

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“…It has been shown that VP stimulates mitogenesis in a number of systems, including mouse Swiss 3T3 cells (Rozengurt et al, 1979), rat bone marrow cells following hemorrhage (Hunt et al, 1977), rat liver cells (Russell & Bucher, 1983), mesangial cell (Ghosh et al, 2001), human osteoblastlike cells (Lagumdzija et al, 2004) and the murine corticotroph tumor cell line, AtT20 (van Wijk et al, 1995). VP has also been shown to increase the number of cells incorporating BrdU in primary cultures of rat anterior pituitary cells (McNicol et al, 1990).…”

Section: Alternative Actions Of Vp In the Pituitary On Mitogenesismentioning

confidence: 99%

The parvocellular vasopressinergic system and responsiveness of the hypothalamic pituitary adrenal axis during chronic stress

Aguilera

Subburaju

Young

et al. 2008

Progress in Brain Research

131

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Vasopressin (VP) secreted from parvocellular neurons of the hypothalamic paraventricular nucleus (PVN) stimulates pituitary ACTH secretion, through interaction with receptors of the V1b subtype (V1bR) in the pituitary corticotroph, mainly by potentiating the stimulatory effects of corticotrophin releasing hormone (CRH). Chronic stress paradigms associated with corticotroph hyperresponsiveness lead to preferential expression of hypothalamic VP over CRH and upregulation of pituitary V1bR, suggesting that VP has a primary role during adaptation of the hypothalamic pituitary adrenal (HPA) axis to long-term stimulation. However, studies using pharmacological of genetic ablation of V1b receptors have shown that VP is required for full ACTH responses to some stressors, but not for the sensitization of ACTH responses to a novel stress observed during chronic stress. Studies using minipump infusion of a peptide V1 antagonist in long-term adrenalectomized rats have revealed that VP mediates proliferative responses in the pituitary. Nevertheless, only a minor proportion of cells undergoing mitogenesis co-express markers for differentiated corticotrophs or precursors, suggesting that new corticotrophs are recruited from yet undifferentiated cells. The overall evidence supports a limited role of VP regulating acute ACTH responses to some acute stressors and points to cell proliferation and pituitary remodeling as alternative roles for the marked increases in parvocellular vasopressinergic activity during prolonged activation of the HPA axis.

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Proliferation of the murine corticotropic tumour cell line AtT20 is affected by hypophysiotrophic hormones, growth factors and glucocorticoids

Cited by 43 publications

References 36 publications

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function

Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro

The parvocellular vasopressinergic system and responsiveness of the hypothalamic pituitary adrenal axis during chronic stress

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