The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

Recouvreux, M. Victoria; Camilletti, María Andrea; Rifkin, Daniel B.; Dı́az-Torga, Graciela

doi:10.1530/joe-15-0451

Cited by 47 publications

(35 citation statements)

References 111 publications

(122 reference statements)

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“…The data reported in this study (summarized in Fig. 8), together with former observations from us and several other groups [2, 39, 51, 54-57], support a new concept for the pathogenesis of prolactinomas. We suggest that PRLR signaling, involving the PRLR per se or effectors thereof, may favor a state of PRL resistance resulting in the downregulation of proapoptotic and antiproliferative effects that are mandatory for pituitary homeostasis, thereby promoting tumor development.…”

Section: Discussionsupporting

confidence: 87%

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

et al. 2018

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Prolactinomas are increasingly viewed as a “problem of signal transduction.” Consequently, the identification of factors and signaling pathways that control lactotrope cell turnover is needed in order to encourage new therapeutic developments. We have previously shown that prolactin (PRL) acts as a proapoptotic and antiproliferative factor on lactotropes, maintaining anterior pituitary cell homeostasis, which contrasts with the classical antiapoptotic and/or proliferative actions exerted by PRL in most other target tissues. We aimed to investigate the PRLR-triggered signaling pathways mediating these nonclassical effects of PRL in the pituitary. Our results suggest that (i) the PRLR/Jak2/STAT5 pathway is constitutively active in GH3 cells and contributes to PRL-induced apoptosis by increasing the Bax/Bcl-2 ratio, (ii) PRL inhibits ERK1/2 and Akt phosphorylation, thereby contributing to its proapoptotic effect, and (iii) the PI3K/Akt pathway participates in the PRL-mediated control of lactotrope proliferation. We hypothesize that the alteration of PRL actions in lactotrope homeostasis due to the dysregulation of any of the mechanisms of actions described above may contribute to the pathogenesis of prolactinomas.

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Section: Discussionsupporting

confidence: 87%

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

et al. 2018

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“…Many studies have shown that targeting some high-frequency hub-molecules in Table 1 has achieved good results in other types of pituitary adenomas. For example, TGFβ1 is used as a novel therapeutic target to treat resistant prolactinomas (66); the microRNA-145 inhibits the activation of the mTOR signaling by targeting AKT3 to suppress the proliferation and invasion of invasive pituitary adenoma cells (67); lncRNA H19 inhibits mTORC1 by disrupting 4E-BP1/Raptor interaction in pituitary tumors (68); and MAPK Pathways act as therapeutic targets in pituitary tumors (69). Because PI3K/Akt/mTOR and ERK/MAPK signaling pathways are significantly dysregulated in NFPA, and these two essential signaling pathways are not only related to rapid proliferation and apoptosis resistance of tumor cells, but also can regulate the activities of many other pathways and then regulate tumor growth in the multiple levels.…”

Section: Mapk Pathways Were Dysregulated In Nfpasmentioning

confidence: 99%

Multiomics-Based Signaling Pathway Network Alterations in Human Non-functional Pituitary Adenomas

Long

Cheng

et al. 2019

Front. Endocrinol.

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Non-functional pituitary adenoma (NFPA) seriously affects hypothanamus-pituitary-target organ axis system, with a series of molecule alterations in the multiple levels of genome, transcriptome, proteome, and post-translational modifications, and those molecules mutually interact in a molecular-network system. Meta analysis coupled with IPA pathway-network program was used to comprehensively analyze nine sets of documented NFPA omics data, including NFPA quantitative transcriptomics data [280 differentially expressed genes (DEGs)], NFPA quantitative proteomics data [50 differentially expressed proteins (DEPs)], NFPA mapping protein data (218 proteins), NFPA mapping protein nitration data (9 nitroproteins and 3 non-nitrated proteins), invasive NFPA quantitative transriptomics data (346 DEGs), invasive NFPA quantitative proteomics data (57 DEPs), control mapping protein data (1469 proteins), control mapping protein nitration data (8 nitroproteins), and control mapping phosphorylation data (28 phosphoproteins). A total of 62 molecular-networks with 861 hub-molecules and 519 canonical-pathways including 54 cancer-related canonical pathways were revealed. A total of 42 hub-molecule panels and 9 canonical-pathway panels were identified to significantly associate with tumorigenesis. Four important molecular-network systems, including PI3K/AKT, mTOR, Wnt, and ERK/MAPK pathway-systems, were confirmed in NFPAs by PTMScan experiments with altered expression-patterns and phosphorylations. Nineteen high-frequency hub-molecules were also validated in NFPAs with PTMScan experiment with at least 2.5-fold changes in expression or phosphorylation, including ERK, ERK1/2, Jnk, MAPK, Mek, p38 MAPK, AKT, PI3K complex, p85, PKC, FAK, Rac, Shc, HSP90, NFκB Complex, histone H3, AP1, calmodulin, and PLC. Furthermore, mTOR and Wnt pathway-systems were confirmed in NFPAs by immunoaffinity Western blot analysis, with significantly decreased expression of PRAS40 and increased phosphorylation levels of p-PRAS40 (Thr246) in mTOR pathway in NFPAs compared to controls, and with the decreased protein expressions of GSK-3β and GSK-3β, significantly increased phosphorylation levels of p-GSK3α (Ser21) and p-GSK3β (Ser9), and increased expression level of β-catenin in Wnt pathway in NFPAs compared to Long et al. Molecular Networks of Non-functional Pituitary Adenomas controls. Those findings provided a comphrensive and large-scale pathway network data for NFPAs, and offer the scientific evidence for insights into the accurate molecular mechanisms of NFPA and discovery of the effective biomarkers for diagnosis, prognosis, and determination of therapeutic targets.

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“…The importance of TGFβ1 in inhibiting lactotroph function is clearly demonstrated by the fact that in human prolactinomas, as well as in animal models of prolactinomas, the TGFβ1 expression and activity were found reduced, suggesting its involvement in the tumor development (Pastorcic et al 1995, Recouvreux et al 2011, 2016.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1

Faraoni

Camilletti

Abeledo-Machado

et al. 2017

Journal of Endocrinology

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Female transgenic mice that overexpress the human chorionic gonadotrophin β subunit (hCGβ+) develop prolactinomas, whereas hCGβ+ males do not. The high levels of circulating hCG induce massive luteinization in the ovary of hCGβ+ females, and progesterone becomes the primary steroid hormone produced, but estradiol remains at physiological level. The involvement of high levels of progesterone in lactotroph proliferation is not clearly understood; hence, the pathogenesis of prolactinomas in hCGβ+ females remains unclear. TGFβ1 is an inhibitor of lactotroph function, and the reduced TGFβ1 activity found in prolactinomas has been proposed to be involved in tumor development. The aim of the present work was to study the role of TGFβ1 in the gender-specific development of prolactinomas in hCGβ+ mice. We compared the expression of different components of the pituitary TGFβ1 system in males and females in this model. We found reduced TGFβ1 levels, reduced expression of TGFβ1 target genes, TGFβ1 receptors, , and in hCGβ+ female pituitaries. However, no differences were found between the transgenic and wild-type male pituitaries. We postulate that decreased pituitary TGFβ1 activity in hCGβ+ females is involved in the development of prolactinomas. In fact, we demonstrated that an treatment carried out for increasing pituitary TGFβ1 activity, was successful in reducing the prolactinoma development, and the hyperprolactinemia in hCGβ+ females. Moreover, the stronger TGFβ1 system found in males could protect them from excessive lactotroph proliferation. Sex differences in the regulation of the pituitary TGFβ1 system could explain gender differences in the incidence of prolactinoma.

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The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas

Cited by 47 publications

References 111 publications

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

JAK2/STAT5 Pathway Mediates Prolactin-Induced Apoptosis of Lactotropes

Multiomics-Based Signaling Pathway Network Alterations in Human Non-functional Pituitary Adenomas

Sex differences in the development of prolactinoma in mice overexpressing hCGβ: role of TGFβ1

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