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Shanghai Jiao Tong University School of Medicine

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.

Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death.

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.

Pituitary Tumor Suppression by Combination of Cabergoline and Chloroquine.

DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a highly conserved kinase whose hyperactivation is critically involved in a variety of human tumors. The role of DEPTOR playing in pituitary adenoma (PA) is largely unknown. Here, we reported that DEPTOR was downregulated in PA tissues, especially dopamine-resistant prolactinomas. Consistently, overexpression of DEPTOR inhibited pituitary tumor GH3 and MMQ cells proliferation in vitro and in vivo, and sensitized GH3 and MMQ cells to cabergoline (CAB), a dopamine agonist (DA). Conversely, knockdown of DEPTOR promoted GH3 and MMQ cells proliferation, and conferred cells resistance to CAB. Mechanistically, DEPTOR inhibited both mTOR Complex 1 (mTORC1) and 2 (mTORC2) activities in PA cells. In addition, DEPTOR expression level was increased to suppress mTOR kinase activity via decreasing E3 ubiquitin ligase, βTrCP1, in response to CAB. Furthermore, DEPTOR enhanced autophagy-dependent cell death to confer cells sensitivity to CAB. Taken together, our results suggest that DEPTOR may be a potential target for the treatment of PAs.

DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma.

Cabergoline is a dopamine agonist that has been used as the first-line treatment option for prolactin-secreting pituitary adenomas for several decades. It not only suppresses hormone production from these prolactinomas, but also causes tumour shrinkage. Recent studies revealed some novel mechanisms by which cabergoline suppresses tumour cell proliferation and induces cell death. In this article, we review the most recent findings in cabergoline studies, focusing on its anti-tumour function. These studies suggest the potential broader clinical use of cabergoline in the treatment of other tumours such as breast cancer, pancreatic neuroendocrine tumours, and lung cancer.

Treatment of Pituitary and Other Tumours with Cabergoline: New Mechanisms and Potential Broader Applications.

Since Costello et al. proposed the concept of pseudocapsule of pituitary neuroendocrine tumors (PitNETs) in 1936, many studies have been published on its occurrence, development process, histopathology, and morphology. Pseudocapsule has been proposed as the anatomical interface between PitNETs and normal pituitary gland, therefore the so-called pseudocapsule-based extracapsular resection (ER) technique was developed as an extracapsular surgery method for PitNETs,which differs from the conventional intracapsular resection (IR). In recent years, ER has also been widely used in patients of different tumor types, sizes, and age groups, because the pseudocapsule can be identified more clearly under the endoscopy. Endoscopic transsphenoidal resection for PitNETs has become the preferred surgical method. We reviewed relevant literatures in the past 10 years, showing that ER could achieve better rate of gross total resection (GTR) and biochemical remission, and reduce tumor recurrence than IR, without increasing postoperative complications. Therefore, the pseudocapsule and ER should be valued by neurosurgeons and actively promoted clinically.

Pseudocapsule and pseudocapsule-based extracapsular resection in pituitary neuroendocrine tumors.

Nonsuicidal self-injury (NSSI) is associated with an increased risk of suicide. As the diagnostic criteria outlined in DSM-5 and other related clinical studies, a patient must have engaged in self-injurious behavior at least 5 times within the past year. However, patients with fewer than 5 self-injury behaviors should not be ignored. Our study included 46 adolescents aged 10-19 years with subthreshold NSSI (sNSSI), along with a control group of 50 healthy adolescents matched for age and other factors. We collected resting-state functional magnetic resonance imaging data and stool samples. The Ottawa Self-Injury Inventory and Deliberate Self-Harm Inventory were used to evaluate self-harm behaviors and addictive features. Local brain activity was assessed using fractional amplitude of low-frequency fluctuations (fALFF), and brain regions with abnormal fALFF were selected as seeds for whole-brain functional connectivity analysis. Stool samples were identified using 16S rDNA amplicon sequencing, and the LDA Effect Size method was used to explore significant differences between grouped samples. Mediation analysis was performed to investigate the brain-gut axis mechanisms of addictive features in sNSSI. We found that compared with healthy controls, sNSSI patients have abnormal fALFF in left thalamus and posterior cingulate cortex, dysconnectivities of left thalamus, and decreased Prevotellaceae. Our results suggested that addictive features of sNSSI may have a brain-gut mechanism. Furtherly, patients with 1-4 NSSI behaviors in the past year should have separate name for identification, such as "subthreshold NSSI".

Brain-gut axis mechanism of subthreshold nonsuicidal self-injury addictive features in adolescents.

Several subtypes of pituitary neuroendocrine tumors (PitNETs), such as acromegaly and Cushing's disease, can result in hypertension. However, whether prolactinoma is associated with this complication remains unknown. Moreover, the effect of treatment with surgery or drugs on blood pressure (BP) is unknown. Herein, a retrospective study reviewed 162 patients with prolactinoma who underwent transsphenoidal surgery between January 2005 and December 2022. BP measurements were performed 1 day before and 5 days after surgery. Accordingly, patients' medical characteristics were recorded. In addition, in situ rat and xenograft nude-mice prolactinoma models have been used to mimic prolactinoma. In vivo BP and serum prolactin (PRL) levels were measured after cabergoline (CAB) administration in both rats and mice. Our data suggest that surgery can effectively decrease BP in prolactinoma patients with or without hypertension. The BP-lowering effect was significantly associated with several variables, including age, sex, disease duration, tumor size, invasion, dopamine agonists (DAs)-resistance, recurrence, and preoperative PRL levels. Moreover, in situ and xenograft prolactinomas induced BP elevation, which was alleviated by CAB treatment without and with a statistical difference in rats and mice, respectively. Thus, surgery or CAB can decrease BP in prolactinoma, indicating that pre- and postoperative BP management becomes essential.

Alternations of Blood Pressure Following Surgical or Drug Therapy for Prolactinomas.

We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.

Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors.

Evaluating the impact of digestive system diseases is vital for devising effective prevention strategies. However, comprehensive reports on the burden of digestive system diseases in China are lacking. Our study aimed to provide an overview of the burden and trends of digestive system diseases from 1990 to 2019 in China and its provinces.

Burden of digestive system diseases in China and its provinces during 1990-2019: Results of the 2019 Global Disease Burden Study.

Skin aging is a complex, multifactorial process involving cellular damage, inflammation, and increased susceptibility to diseases. Despite its importance, the role of SPRY1 in skin aging remains poorly understood. This study aims to investigate the function of SPRY1 in skin aging, particularly its impact on macrophage M1 polarization, and explore its potential as a therapeutic target for mitigating skin aging and melanoma.

ArticleTotal : 2	Year
Publication title	2025
Publication title	2025

Article	Year
Activation of DRD5 (dopamine receptor D5) inhibits tumor growth by autophagic cell death. Autophagy\| PubMed ID: 28613975	2017
Pituitary Tumor Suppression by Combination of Cabergoline and Chloroquine. The Journal of clinical endocrinology and metabolism\| PubMed ID: 28973192	2017
DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma. Cancer letters\| PubMed ID: 31176743	2019
Treatment of Pituitary and Other Tumours with Cabergoline: New Mechanisms and Potential Broader Applications. Neuroendocrinology\| PubMed ID: 31597135	2020
Pseudocapsule and pseudocapsule-based extracapsular resection in pituitary neuroendocrine tumors. Frontiers in endocrinology\| PubMed ID: 36465639	2022
Brain-gut axis mechanism of subthreshold nonsuicidal self-injury addictive features in adolescents. Cerebral cortex (New York, N.Y. : 1991)\| PubMed ID: 37724424	2023
Alternations of Blood Pressure Following Surgical or Drug Therapy for Prolactinomas. Cancers\| PubMed ID: 38398117	2024
Therapeutic potential of targeting Nrf2 by panobinostat in pituitary neuroendocrine tumors. Acta neuropathologica communications\| PubMed ID: 38637883	2024
Burden of digestive system diseases in China and its provinces during 1990-2019: Results of the 2019 Global Disease Burden Study. Chinese medical journal\| PubMed ID: 39138597	2024
SPRY1 regulates macrophage M1 polarization in skin aging and melanoma prognosis. Translational oncology\| PubMed ID: 40023001	2025

Xun Zhang

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