Chronic stress accelerates glioblastoma progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop.

BACKGROUND: After diagnosis, glioblastoma (GBM) patients undertake tremendous psychological problems such as anxiety and depression, which may contribute to GBM progression. However, systematic study about the relationship between depression and GBM progression is still lacking. METHODS: Chronic unpredictable mild stress and chronic restrain stress were used to mimic human depression in mice. Human GBM cells and intracranial GBM model were used to assess the effects of chronic stress on GBM growth. Targeted neurotransmitter sequencing, RNA-seq, immunoblotting and immunohistochemistry were used to detect the related molecular mechanism. RESULTS: Chronic stress promoted GBM progression and up-regulated the level of dopamine (DA) and its receptor type 2 (DRD2) in tumor tissues. Down-regulation or inhibition of DRD2 abolished the promoting effect of chronic stress on GBM progression. Mechanistically, the elevated DA and DRD2 activated ERK1/2 and consequently inhibited GSK3ß activity, leading to ß-catenin activation. Meanwhile, the activated ERK1/2 up-regulated tyrosine hydroxylase (TH) level in GBM cells and then promoted DA secretion, forming an autocrine positive feedback loop. Remarkably, patients with high-depression exhibited high DRD2 and ß-catenin levels, which showed poor prognosis. Additionally, DRD2 specific inhibitor pimozide combined with temozolomide synergistically inhibited GBM growth. CONCLUSIONS: Our study revealed that chronic stress accelerates GBM progression via DRD2/ERK/ß-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with ß-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.

Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.

Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial-omics, and a synthetic hydrogel-based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs are defined. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPCs. The ECM type distinctly regulates the response to small-molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft in immunocompromised mice showed strong anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of therapies to overcome resistance.

Dopamine receptor D2S gene transfer improves the sensitivity of GH3 rat pituitary adenoma cells to bromocriptine.

Bromocriptine, a dopamine agonist (DA), has been used in the treatment of prolactinomas. Recent studies have indicated that dopamine 2 receptor short isoform (D2S) may play an important role in suppressing PRL synthesis and prolactinoma cell growth under DA treatment. In the current study, we investigated the role of D2S in the therapeutic action of bromocriptine in GH3 using both in vitro and in vivo approaches. Infection of adenovirus-D2S increased D2S expression in GH3 cells (P<0.05). D2S expression significantly decreased the GH3 cell viability subjected to bromocriptine treatment in vitro (P<0.05). In nude mice, adenovirus-D2S transfection sensitized GH3 xenograft to bromocriptine treatment evidenced by the significant inhibition of D2S expressed tumor growth as compared with vector control. Furthermore, decrease of Bcl-2 expression, increase of Bax, and active Caspase-3 were found in D2S expressed GH3 xenograft subjected to bromocriptine treatment. In summary, our study indicates that D2S expression plays a critical role in the therapeutic action of bromocriptine in pituitary adenomas and that adenovirus-mediated D2S gene transfer combined with bromocriptine may provide a novel treatment for DA-resistant prolactinomas.

Utilization of health care services by patients with chronic obstructive pulmonary disease.

In order to identify healthcare resource use patterns associated with chronic obstructive pulmonary disease (COPD), resource utilization (RU) data collection was integrated into a randomized, double-blind placebo-controlled study of Viozan (sibenadet HCl). This study enrolled patients with symptomatic, smoking-related COPD, randomized to receive sibenadet or placebo for a 52-week treatment period. A questionnaire establishing typical pre-trial, COPD-related RU was completed by each patient. Subsequent data were collected by means of an Interactive Voice Response System (IVRS) at 30-day intervals (14 time points) during the study and in the follow-up period. The IVRS system facilitated data collection and minimized inconvenience to the patient. Compliance with the requirement to record details of the healthcare services during the year-long study was high. No overall trend for lower RU was associated with sibenadet therapy, which correlates with the lack of sustained clinical effect seen in studies conducted concurrently. These data do, however, provide valuable information on RU associated with COPD and insights into adjustments associated with changes in disease course. Physicians were seen to be the most common source of care for patients with COPD and more of the patients with severe COPD (stage III) than mild (stage I) were seen to utilize the most expensive resources (e.g. inpatient hospital care). For those patients who experienced an exacerbation during the trial (irrespective of treatment group), resource use was increased during the periods when an exacerbation was reported when compared with the periods before or after an exacerbation. The proportion of cases attending the physician doubled and with a trip to the Emergency Room (ER) increased approximately ninefold during the reporting period in which the exacerbation occurred compared with the previous month. This study has shown that use of an IVRS, even in elderly patients, is an effective means of gathering RU data over long periods. The study findings suggest that the advent of effective therapeutic interventions, particularly any with the ability to minimize exacerbations and limit disease progression, could impact on the health care services used and potentially reduce associated costs.