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1.
J Clin Endocrinol Metab ; 102(10): 3692-3703, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28973192

ABSTRACT

Context: The dopamine agonist cabergoline (CAB) has been used widely in the treatment of prolactinomas and other types of pituitary adenomas, but its clinical use is hampered by intolerance in some patients with prolactinoma and lack of effectiveness in other pituitary tumor types. Chloroquine (CQ) is an old drug widely used to treat malaria. Recent studies, including our own, have revealed that CAB and CQ are involved in induction of autophagy and activation of autophagic cell death. Objective: To test whether CAB and CQ can function cooperatively to suppress growth of pituitary adenomas as well as other cancers. Results: In vitro studies using the rat pituitary tumor cell lines MMQ and GH3, human pituitary tumor cell primary cultures, and several human cancer cell lines showed that CQ enhanced suppression of cell proliferation by CAB. These results were confirmed in in vivo xenograft models in nude mice and estrogen-induced rat prolactinomas. To understand the mechanism of combined CAB and CQ action, we established a low-CAB-dose condition in which CAB was able to induce autophagy but failed to suppress cell growth. Addition of CQ to low-dose CAB blocked normal autophagic cycles and induced apoptosis, evidenced by the further accumulation of p62/caspase-8/LC3-II. Conclusion: The data suggest that combined use of CAB and CQ may increase clinical effectiveness in treatment of human pituitary adenomas, as well as other cancers, making it an attractive option in tumor and cancer therapies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chloroquine/administration & dosage , Ergolines/administration & dosage , Pituitary Neoplasms/drug therapy , Prolactinoma/drug therapy , Animals , Cabergoline , Cell Death/drug effects , Cells, Cultured , Female , Hep G2 Cells , Humans , Mice , Mice, Nude , Pituitary Neoplasms/pathology , Prolactinoma/pathology , Rats , Rats, Inbred F344 , Xenograft Model Antitumor Assays
2.
Autophagy ; 13(8): 1404-1419, 2017 Aug 03.
Article in English | MEDLINE | ID: mdl-28613975

ABSTRACT

Dopamine agonists such as bromocriptine and cabergoline have been successfully used in the treatment of pituitary prolactinomas and other neuroendocrine tumors. However, their therapeutic mechanisms are not fully understood. In this study we demonstrated that DRD5 (dopamine receptor D5) agonists were potent inhibitors of pituitary tumor growth. We further found that DRD5 activation increased production of reactive oxygen species (ROS), inhibited the MTOR pathway, induced macroautophagy/autophagy, and led to autophagic cell death (ACD) in vitro and in vivo. In addition, DRD5 protein was highly expressed in the majority of human pituitary adenomas, and treatment of different human pituitary tumor cell cultures with the DRD5 agonist SKF83959 resulted in growth suppression, and the efficacy was correlated with the expression levels of DRD5 in the tumors. Furthermore, we found that DRD5 was expressed in other human cancer cells such as glioblastomas, colon cancer, and gastric cancer. DRD5 activation in these cell lines suppressed their growth, inhibited MTOR activity, and induced autophagy. Finally, in vivo SKF83959 also inhibited human gastric cancer cell growth in nude mice. Our studies revealed novel mechanisms for the tumor suppressive effects of DRD5 agonists, and suggested a potential use of DRD5 agonists as a novel therapeutic approach in the treatment of different human tumors and cancers.


Subject(s)
Autophagy , Pituitary Neoplasms/metabolism , Pituitary Neoplasms/pathology , Receptors, Dopamine D5/metabolism , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/analogs & derivatives , 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine/pharmacology , Animals , Autophagosomes/drug effects , Autophagosomes/metabolism , Autophagosomes/ultrastructure , Autophagy/drug effects , Cabergoline , Cell Line, Tumor , Cell Proliferation/drug effects , Ergolines/pharmacology , Ergolines/therapeutic use , Humans , Mice, Nude , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/ultrastructure , Rats , Reactive Oxygen Species/metabolism , Receptors, Dopamine D5/genetics , Superoxide Dismutase/metabolism , TOR Serine-Threonine Kinases/metabolism
3.
Endocrine ; 52(3): 641-51, 2016 Jun.
Article in English | MEDLINE | ID: mdl-26662185

ABSTRACT

Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6, n = 8, vs 13.1 ± 2.8, n = 17, p = 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.


Subject(s)
Dopamine Agonists/therapeutic use , Drug Resistance, Neoplasm/genetics , Neoplasm Proteins/physiology , Neovascularization, Pathologic/genetics , Pituitary Neoplasms/pathology , Prolactinoma/pathology , Proteoglycans/physiology , Adolescent , Adult , Aged , Animals , Bromocriptine/pharmacology , Bromocriptine/therapeutic use , Case-Control Studies , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cell Survival/drug effects , Cell Survival/genetics , Cells, Cultured , Dopamine Agonists/pharmacology , Female , Gene Knockdown Techniques , Human Umbilical Vein Endothelial Cells , Humans , Male , Middle Aged , Neoplasm Proteins/antagonists & inhibitors , Pituitary Neoplasms/blood supply , Pituitary Neoplasms/genetics , Prolactinoma/blood supply , Prolactinoma/genetics , Proteoglycans/antagonists & inhibitors , Rats , Young Adult
4.
Brain Pathol ; 26(1): 31-42, 2016 Jan.
Article in English | MEDLINE | ID: mdl-25758142

ABSTRACT

Heat shock protein 47 (HSP47) is a collagen-binding protein, which has been recently found to express in glioma vessels. However, the expression profile of HSP47 in glioma patients and the underlying mechanisms of HSP47 on glioma angiogenesis are not fully explored. In the current study, we found that expression of HSP47 in glioma vessels was correlated with the grades of gliomas. HSP47 knockdown by siRNAs significantly decreased cell viability in vitro and tumor volume in vivo; moreover, it reduced the microvessel density (MVD) by CD31 immunohistochemistry in vivo. HSP47 knockdown significantly inhibited tube formation, invasion and proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, conditional medium derived from HSP47 knockdown cells significantly inhibited HUVECs tube formation and migration, while it increased chemosensitivity of HUVECs cells to Avastin. Silencing of HSP47 decreased VEGF expression in glioma cells consistently, and reduced glioma vasculature. Furthermore, HSP47 promoted glioma angiogenesis through HIF1α-VEGFR2 signaling. The present study demonstrates that HSP47 promotes glioma angiogenesis and highlights the importance of HSP47 as an attractive therapeutic target of GBM.


Subject(s)
Brain Neoplasms/pathology , Glioma/pathology , HSP47 Heat-Shock Proteins/metabolism , Neovascularization, Pathologic/etiology , Neovascularization, Pathologic/metabolism , Tumor Cells, Cultured/drug effects , Cell Movement/genetics , Cell Proliferation/genetics , Endothelial Cells/metabolism , Endothelial Cells/pathology , Gene Expression Regulation, Neoplastic/genetics , HSP47 Heat-Shock Proteins/genetics , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Male , Microvessels/metabolism , Microvessels/pathology , Middle Aged , Mitogen-Activated Protein Kinase 3/metabolism , Neovascularization, Pathologic/genetics , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptor, ErbB-2/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Wound Healing/genetics
5.
Oncotarget ; 6(36): 39329-41, 2015 Nov 17.
Article in English | MEDLINE | ID: mdl-26513171

ABSTRACT

Cabergoline (CAB), the first-line drug for treatment of prolactinomas, is effective in suppressing prolactin hypersecretion, reducing tumor size, and restoring gonadal function. However, mechanisms for CAB-mediated tumor shrinkage are largely unknown. Here we report a novel cytotoxic mechanism for CAB. CAB induced formation of autophagosome in rat pituitary tumor MMQ and GH3 cells at the early stage through inhibiting mTOR pathway, resulting in higher conversion rates of LC3-I to LC3-II, GFP-LC3 aggregation, and increased autophagosome formation. Interestingly, CAB treatment augmented lysosome acidification and resulted in impaired proteolytic degradation within autolysosomes. This blocked the autophagic flux, leading to the accumulation of p62 aggregation and undigested autolysosomes. Knockdown of ATG7, ATG5, or Becn1, could significantly rescue the CAB-mediated cell death of MMQ cells (p < 0.05). CAB-induced autophagy and blockade of autophagy flux participated in antitumoral action in vivo. In conclusion, our study provides evidence that CAB concomitantly induces autophagy and inhibits the autophagic flux, leading to autophagy-dependent cell death. These findings elucidate novel mechanisms for CAB action.


Subject(s)
Antineoplastic Agents/pharmacology , Ergolines/pharmacology , Prolactinoma/drug therapy , TOR Serine-Threonine Kinases/metabolism , Animals , Apoptosis/drug effects , Autophagy/drug effects , Cabergoline , Cell Death/drug effects , Female , Heterografts , Mice , Mice, Nude , Prolactinoma/genetics , Prolactinoma/metabolism , Prolactinoma/pathology , Rats , TOR Serine-Threonine Kinases/genetics , Transfection
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