Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Cancer Discov ; 11(7): 1808-1825, 2021 07.
Article in English | MEDLINE | ID: mdl-33653692

ABSTRACT

Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer-associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs-it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging. SIGNIFICANCE: Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth.This article is highlighted in the In This Issue feature, p. 1601.


Subject(s)
Cancer-Associated Fibroblasts , Carcinoma, Pancreatic Ductal/metabolism , Pancreatic Neoplasms/metabolism , Stromal Cells , Tumor Microenvironment , Animals , Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism , Carcinoma, Pancreatic Ductal/pathology , Humans , Mice , Mice, Inbred C57BL , Pancreatic Neoplasms/pathology , Pinocytosis , Rho Guanine Nucleotide Exchange Factors/metabolism , Signal Transduction
2.
Cancer Discov ; 10(6): 822-835, 2020 06.
Article in English | MEDLINE | ID: mdl-32200349

ABSTRACT

Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium-hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC. SIGNIFICANCE: NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a "proton sink" for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.See related commentary by Ward and DeNicola, p. 768.This article is highlighted in the In This Issue feature, p. 747.


Subject(s)
Carcinoma, Pancreatic Ductal/pathology , Golgi Apparatus/metabolism , Pancreatic Neoplasms/pathology , Sodium-Hydrogen Exchangers/metabolism , Homeostasis , Humans , Hydrogen-Ion Concentration
3.
Front Neuroendocrinol ; 50: 118-122, 2018 07.
Article in English | MEDLINE | ID: mdl-29074127

ABSTRACT

Prolactinomas are the most frequent functioning pituitary adenomas, and sex differences in tumor size, behavior and incidence have been described. These differences have been associated with earlier diagnosis in woman, as well as with serum estradiol levels. Experimental models of prolactinomas in rodents also show a higher incidence in females, and recent findings suggest that gender differences in the transforming growth factor beta 1 (TGFß1) system might be involved in the sex-specific development of prolactinomas in these models. The aim of this review is to summarize the literature supporting the important role of TGFß1 as a local modulator of pituitary lactotroph function and to provide recent evidence for TGFß1 involvement in the sex differences found in prolactinoma development in animal models.


Subject(s)
Pituitary Neoplasms/metabolism , Prolactinoma/metabolism , Sex Characteristics , Transforming Growth Factor beta1/metabolism , Animals , Female , Humans , Male
4.
Endocrinology ; 158(7): 2255-2268, 2017 07 01.
Article in English | MEDLINE | ID: mdl-28444169

ABSTRACT

Prostate cancer (PCa) growth is mainly driven by androgen receptor (AR), and tumors that initially respond to androgen deprivation therapy (ADT) or AR inhibition usually relapse into a more aggressive, castration-resistant PCa (CRPC) stage. Circulating growth hormone (GH) has a permissive role in PCa development in animal models and in human PCa xenograft growth. As GH and GH receptor (GHR) are both expressed in PCa cells, we assessed whether prostatic GH production is linked to AR activity and whether GH contributes to the castration-resistant phenotype. Using online datasets, we found that GH is highly expressed in human CRPC. We observed increased GH expression in castration-resistant C4-2 compared with castration-sensitive LNCaP cells as well as in enzalutamide (MDV3100)-resistant (MDVR) C4-2B (C4-2B MDVR) cells compared with parental C4-2B. We describe a negative regulation of locally produced GH by androgens/AR in PCa cells following treatment with AR agonists (R1881) and antagonists (enzalutamide, bicalutamide). We also show that GH enhances invasive behavior of CRPC 22Rv1 cells, as reflected by increased migration, invasion, and anchorage-independent growth, as well as expression of matrix metalloproteases. Moreover, GH induces expression of the AR splice variant 7, which correlates with antiandrogen resistance, and also induces insulinlike growth factor 1, which is implicated in PCa progression and ligand-independent AR activation. In contrast, blockade of GH action with the GHR antagonist pegvisomant reverses these effects both in vitro and in vivo. GH induction following ADT or AR inhibition may contribute to CRPC progression by bypassing androgen growth requirements.


Subject(s)
Human Growth Hormone/genetics , Prostate/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Receptors, Androgen/physiology , Androgen Antagonists/pharmacology , Androgens/pharmacology , Animals , Benzamides , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Heterografts , Human Growth Hormone/analogs & derivatives , Human Growth Hormone/metabolism , Human Growth Hormone/pharmacology , Humans , Male , Mice , Mice, Nude , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Prostate/drug effects , Prostatic Neoplasms/pathology
5.
J Endocrinol ; 228(3): R73-83, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26698564

ABSTRACT

Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor ß1 (TGFß1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFß1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFß1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFß receptors. Pituitary TGFß1 activity and the expression of different components of the TGFß1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFß1 activity as well as reduced expression of several components of the TGFß1 system. Therefore, restoration of TGFß1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFß1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFß1 activity as an effective treatment in experimental prolactinomas.


Subject(s)
Drug Resistance, Neoplasm , Pituitary Gland/metabolism , Pituitary Neoplasms/drug therapy , Prolactinoma/drug therapy , Transforming Growth Factor beta1/drug effects , Transforming Growth Factor beta1/physiology , Animals , Cell Proliferation , Dopamine/physiology , Dopamine Agonists/therapeutic use , Estradiol/physiology , Humans , Lactotrophs/physiology , Pituitary Neoplasms/physiopathology , Prolactin/antagonists & inhibitors , Prolactin/metabolism , Prolactinoma/physiopathology
6.
Endocrinology ; 154(11): 4192-205, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24008346

ABSTRACT

Dopamine and estradiol interact in the regulation of lactotroph cell proliferation and prolactin secretion. Ablation of the dopamine D2 receptor gene (Drd2(-/-)) in mice leads to a sexually dimorphic phenotype of hyperprolactinemia and pituitary hyperplasia, which is stronger in females. TGF-ß1 is a known inhibitor of lactotroph proliferation. TGF-ß1 is regulated by dopamine and estradiol, and it is usually down-regulated in prolactinoma experimental models. To understand the role of TGF-ß1 in the gender-specific development of prolactinomas in Drd2(-/-) mice, we compared the expression of different components of the pituitary TGF-ß1 system, including active cytokine content, latent TGF-ß-binding protein isoforms, and possible local TGF-ß1 activators, in males and females in this model. Furthermore, we evaluated the effects of dopamine and estradiol administration to elucidate their role in TGF-ß1 system regulation. The expression of active TGF-ß1, latent TGF-ß-binding protein isoforms, and several putative TGF-ß1 activators evaluated was higher in male than in female mouse pituitary glands. However, Drd2(-/-) female mice were more sensitive to the decrease in active TGF-ß1 content, as reflected by the down-regulation of TGF-ß1 target genes. Estrogen and dopamine caused differential regulation of several components of the TGF-ß1 system. In particular, we found sex- and genotype- dependent regulation of active TGF-ß1 content and a similar expression pattern for 2 of the putative TGF-ß1 activators, thrombospondin-1 and kallikrein-1, suggesting that these proteins could mediate TGF-ß1 activation elicited by dopamine and estradiol. Our results indicate that (1) the loss of dopaminergic tone affects the pituitary TGF-ß1 system more strongly in females than in males, (2) males express higher levels of pituitary TGF-ß1 system components including active cytokine, and (3) estradiol negatively controls most of the components of the system. Because TGF-ß1 inhibits lactotroph proliferation, we propose that the higher levels of the TGF-ß1 system in males could protect or delay the development of prolactinomas in Drd2(-/-) male mice.


Subject(s)
Pituitary Gland/metabolism , Prolactinoma/metabolism , Transforming Growth Factor beta1/metabolism , Animals , Female , Gene Expression Regulation/physiology , Genotype , Integrins/genetics , Integrins/metabolism , Male , Mice , Mice, Knockout , Pituitary Neoplasms/metabolism , Receptors, Dopamine D2/genetics , Receptors, Dopamine D2/metabolism , Sex Factors , Thrombospondin 1/genetics , Thrombospondin 1/metabolism , Tissue Kallikreins/genetics , Tissue Kallikreins/metabolism , Transforming Growth Factor beta1/genetics
7.
Endocrinology ; 153(8): 3861-71, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22700773

ABSTRACT

Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-ß1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-ß1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas.


Subject(s)
Oligopeptides/therapeutic use , Prolactinoma/drug therapy , Thrombospondin 1/chemistry , Transforming Growth Factor beta1/metabolism , Animals , Diethylstilbestrol/toxicity , Female , Oligopeptides/chemistry , Prolactinoma/chemically induced , Prolactinoma/metabolism , Rats , Rats, Sprague-Dawley
8.
Endocrinology ; 152(7): 2722-30, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21521749

ABSTRACT

Dopamine, acting through the dopamine type 2 receptor (Drd2), is the main inhibitor of pituitary prolactin (PRL) secretion and lactotroph proliferation. TGF-ß1 is involved, at least in part, in mediating these actions. It was described that TGF-ß1 synthesis in rat pituitary lactotrophs is up-regulated by dopamine and down-regulated by estradiol. TGF-ß1 is secreted as a large latent complex. The local regulation of cytokine activation in the pituitary has not yet been explored. In this work, we studied pituitary active and total TGF-ß1 content, as well as TGF-ß1 mRNA, and the in vivo role of dopamine and estradiol on pituitary TGF-ß1 levels. Adult female mice (wild type), and female mice with a null mutation in the Drd2 (Drd2(-/-)), were used. The loss of dopaminergic tone induced a decrease in TGF-ß1 mRNA expression, in active and total cytokine content, and in TGF-ß type II receptor expression. Dopamine regulation of pituitary TGF-ß1 activation process was inferred by the inhibition of active cytokine by in vivo sulpiride treatment. Interestingly, in the absence of dopaminergic tone, estradiol induced a strong increase in active TGF-ß1. PRL secretion correlated with active, but not total cytokine. TGF-ß1 inhibitory action on lactotroph proliferation and PRL secretion was decreased in Drd2(-/-) pituitary cells, in correlation with decreased TGF-ß type II receptor. The study of the TGF-ß1 activation process and its regulation is essential to understand the cytokine activity. As an intermediary of dopamine inhibition of lactotroph function, TGF-ß1 and local activators may be important targets in the treatment of dopamine agonist-resistant prolactinomas.


Subject(s)
Dopamine Agonists/pharmacology , Dopamine Antagonists/pharmacology , Estradiol/analogs & derivatives , Gene Expression Regulation/drug effects , Pituitary Gland, Anterior/drug effects , Receptors, Dopamine D2/metabolism , Transforming Growth Factor beta1/metabolism , Animals , Cell Proliferation , Cells, Cultured , Dopamine Agonists/therapeutic use , Dopamine Antagonists/therapeutic use , Dopamine D2 Receptor Antagonists , Estradiol/pharmacology , Estradiol/therapeutic use , Female , Hyperprolactinemia/drug therapy , Lactotrophs/drug effects , Lactotrophs/metabolism , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Pituitary Gland, Anterior/cytology , Pituitary Gland, Anterior/metabolism , Prolactin/blood , Prolactin/metabolism , Protein Serine-Threonine Kinases/metabolism , RNA, Messenger/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/genetics , Receptors, Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...