Chronic stress accelerates glioblastoma progression via DRD2/ERK/β-catenin axis and Dopamine/ERK/TH positive feedback loop
-
Published:2023-07-07
Issue:1
Volume:42
Page:
-
ISSN:1756-9966
-
Container-title:Journal of Experimental & Clinical Cancer Research
-
language:en
-
Short-container-title:J Exp Clin Cancer Res
Author:
Wang Yan, Wang Xiang, Wang Kai, Qi Ji, Zhang Yu, Wang Xu, Zhang Long, Zhou Yi, Gu Linbo, Yu Rutong, Zhou XiupingORCID
Abstract
Abstract
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 GSK3β activity, leading to β-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 β-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/β-catenin axis and Dopamine/ERK/TH positive feedback loop. DRD2 together with β-catenin may serve as a potential predictive biomarker for worse prognosis as well as therapeutic target of GBM patients with depression.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference35 articles.
1. Tan AC, Ashley DM, Lopez GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70:299–312. 2. Bortolato B, Hyphantis TN, Valpione S, Perini G, Maes M, Morris G, Kubera M, Kohler CA, Fernandes BS, Stubbs B, Pavlidis N, Carvalho AF. Depression in cancer: The many biobehavioral pathways driving tumor progression. Cancer Treat Rev. 2017;52:58–70. 3. Wen Y, Zhang Y, Li J, Luo F, Huang Z, Liu K. Low concentration trifluoperazine promotes proliferation and reduces calcium-dependent apoptosis in glioma cells. Sci Rep. 2018;8:1147. 4. A.M. Bielecka, E. Obuchowicz, Antidepressant drugs can modify cytotoxic action of temozolomide, Eur J Cancer Care (Engl), 26 (2017). 5. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44.
|
|