Aphidicolin inhibits cell proliferation &lt;i&gt;via&lt;/i&gt; the p53-GADD45&amp;beta; pathway in AtT-20 cells

Kageyama, Kazunori; Sugiyama, Aya; Murasawa, Shingo; Asari, Yuko; Niioka, Kanako; Osuga, Yutaka; Daimon, Makoto

doi:10.1507/endocrj.ej15-0084

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…Because the drug does not affect the cell viability of other endocrine or nonendocrine cells [19], this inhibitor shows a specific effect on pituitary tumor cells. Decreased ACTH levels might be also achieved by inhibiting tumor cell proliferation and ACTH synthesis [20].…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation

et al. 2020

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Cushing's disease is primarily caused by autonomic hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. In Cushing's disease, mutations in the ubiquitin-specific protease 8 (USP8) have been detected. These mutations are associated with hyperactivation of USP8 that prevent epidermal growth factor receptor (EGFR) degradation. This leads to increased EGFR stability and results in the maintenance of EGFR signaling in Cushing's disease. USP8 inhibitors can suppress the growth of various tumors. In this study, the effects of a potent USP8 inhibitor, DUBs-IN-2, on ACTH production and cell proliferation were examined in mouse corticotroph tumor (AtT-20) cells. Proopiomelanocortin (Pomc) mRNA levels and ACTH levels were decreased in AtT-20 cells by DUBs-IN-2. Further, cell proliferation was inhibited, and apoptosis was induced by DUBs-IN-2. Transcript levels of pituitary tumor-transforming gene 1 (Pttg1), a pituitary tumor growth marker, were increased; and transcript levels of stress response growth arrest and DNA damageinducible 45 (Gadd45β) and Cdk5 and ABL enzyme substrate 1 (Cables1) mRNA levels were increased in response to the drug. Gadd45β or Cables1 knockdown partially inhibited the DUBs-IN-2-induced decrease in cell proliferation, but not Pomc mRNA levels. Both GADD45β and CABLES1 may be responsible, at least in part, for the USP8-induced suppression of corticotroph tumor cell proliferation. USP-8 may be a new treatment target in Cushing's disease.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation

et al. 2020

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“…The AtT-20 cell line is characterized by autonomous ACTH secretion; therefore, it might be difficult to further increase its ACTH secretion. Moreover, various factors, such as an inhibitor of the Jak2 signaling pathway (Lapatinib), 65 somatostatin analog (SOM230) 66 and DNA replication inhibitor (Aphidiloclin), 67 have been proven to decrease ACTH secretion of this cell line. It is also surprising and incomprehensible to note that Fk866 added to the AtT-20 cell culture also did not change ACTH secretion by these cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Nampt (eNampt/Visfatin/PBEF) directly and indirectly stimulates ACTH and CCL2 protein secretion from isolated rat corticotropes

et al. 2021

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Background. Nicotinamide phosphoribosyltransferase (Nampt/visfatin/PBEF) acts both as an enzyme in the nicotinamide adenine dinucleotide (NAD) synthesis pathway as well as an extracellular hormone (eNampt). Among its effects, eNampt exerts potent pro-inflammatory effects. We have recently shown that, in rats, eNampt stimulates corticosterone secretion by acting through the pituitary rather than the hypothalamus.Objectives. To investigate the mechanism of action of eNampt on the secretion of adrenocorticotropic hormone (ACTH) and chemokine (C-C motif) ligand 2 (CCL2), which are cytokines secreted by pituitary neuroendocrine tumors. Materials and methods.The research was carried out on the AtT-20 murine cell line, primary rat pituitary cell culture, isolated pituitary corticotropes, and in vivo. The effects of the performed experiments were examined using the following methods: gene expression profiling using microarrays, quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA).Results. The results suggest that eNampt stimulates ACTH secretion from rat corticotropes both directly and indirectly. Indirect action most likely occurs through interleukin (IL)-6 secreted by folliculostellate cells of the pituitary gland. In isolated ACTH cells of the rat pituitary gland, eNampt stimulates the expression of genes involved in the immune response. Among them, the protein encoded by the CCL2 gene seems to also be involved in the regulation of corticotropin-releasing hormone (CRH)-dependent metabolism. Unlike rat corticotropes, murine AtT-20 corticotropic cells do not react to either eNampt or Fk866 (the inhibitor of Nampt enzymatic action).Conclusions. The eNampt stimulates the secretion of ACTH from rat corticotropes indirectly and directly, likely by stimulating IL-6 secretion from folliculostellate cells of the pituitary gland. This effect was not observed in the AtT-20 corticotropic cell cancer cell line.

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“…The ACTH levels in the medium might be less decreased, compared with cell proliferation. The decreased ACTH levels in Effects of lapatinib on corticotrophs the medium, therefore, may be caused mainly by decreases in cell proliferation and partially by those in ACTH synthesis [19]. Similar to that of gefitinib, lapatinib also binds to the ATP binding pocket of both EGFR and HER2 protein kinase [11].…”

Section: Discussionmentioning

confidence: 99%

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells

et al. 2019

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Cushing's disease is almost always caused by hypersecretion of adrenocorticotropic hormone (ACTH) from a pituitary adenoma. A mutation in the deubiquitinase gene USP8 has been found in human ACTH-producing pituitary adenoma cells. This mutational hotspot hyperactivates USP8, rescuing epidermal growth factor receptor (EGFR) from lysosomal degradation and ensuring its sustained signaling in Cushing's disease. An EGFR inhibitor would be an effective anti-tumor agent in EGFR-related tumors. We investigated the effect of a potent dual tyrosine kinase inhibitor, lapatinib, on ACTH production and cell proliferation in AtT-20 mouse corticotroph tumor cells. Lapatinib decreased proopiomelanocortin (Pomc) mRNA levels and ACTH levels in AtT-20 cells and also inhibited cell proliferation, induced apoptosis, and decreased pituitary tumor-transforming gene 1 (Pttg1), a hallmark of pituitary tumors, mRNA levels. KSN/Slc nude mice were subcutaneously inoculated with AtT-20 cells. After 1 week, the mice were randomized either to control or lapatinib groups. The inhibitor decreased the tumor weight of AtT-20 allografts in vivo versus control mice. Lapatinib also significantly decreased Pomc and Pttg1 mRNA levels in the tumor and plasma ACTH and corticosterone levels in vivo. Thus, lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells. An EGFR-targeting therapy could be an important treatment for Cushing's disease.

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Aphidicolin inhibits cell proliferation <i>via</i> the p53-GADD45β pathway in AtT-20 cells

Cited by 10 publications

References 20 publications

Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation

Ubiquitin-specific protease 8 inhibitor suppresses adrenocorticotropic hormone production and corticotroph tumor cell proliferation

Extracellular Nampt (eNampt/Visfatin/PBEF) directly and indirectly stimulates ACTH and CCL2 protein secretion from isolated rat corticotropes

Lapatinib decreases the ACTH production and proliferation of corticotroph tumor cells

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