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Cited by 261Cancer, Stress, Anesthesia, and Immune ResponseReceptor Mechanisms and SignalingGastric Cancer Management and Outcomes

Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2

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Zhang, Xuan, Zhang, Yi, He, Zhongyuan, Yin, Kai, Li, Bowen, Zhang, Lu, Xu, Zekuan·2019·Cell Death & Disease
DOI 10.1038/s41419-019-2030-2PMC PMC6797812
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Abstract

An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation and blockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays. Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonists significantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition, chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest β2 blockade as a novel strategy to complement existing therapies for GC.

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Crossref · 10.1038/s41419-019-2030-2

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  • β-adrenergic signaling promotes EMT and increases metastatic potential in cancer cells via VEGF/MMP and STAT3/ERK/MAPK pathways.

    “For example, β-adrenergic signaling has been implicated in promoting EMT and increasing the metastatic potential in cancer cells via the VEGF/MMP and STAT3/ERK/MAPK pathways.321”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [321]

    The Discussion (page unavailable) reports that ADRB2 activation increased liver and lung metastasis of gastric cancer cells in mice and increased VEGF and MMP expression. The Results section on STAT3 and ERK/JNK/MAPK (page unavailable) reports activation of those signals, but links the inhibitor experiments specifically to cell growth. Our copy does not establish that β-adrenergic signaling promotes EMT or that these pathways mediate the observed metastasis. (LLM, conf=0.88)

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  • ADRB2 antagonists propranolol and ICI118,551 suppress gastric cancer progression by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors NF-κB, AP-1, and STAT3.

    “ADRB2 antagonists such as propranolol and ICI118,551 suppressed gastric cancer progression by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, and STAT3 (14).”

    From Chronic Stress Promotes Cancer Development (2020) · cites this paper as [14]

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Research works printed but not linked: 2

  1. [12]Xu, Z. et al. Role of the autonomic nervous system in the tumor micro-environment and its therapeutic potential. Curr. Pharm. Des.23, 1687–1692 (22017). 27784236
  2. [37]Qin, J. F. et al. Adrenergic receptor β2 activation by stress promotes breastcancer progression through macrophages M2 polarization in tumormicroenvironment. BMB Rep.48, 295 (2015). PMC4578570 25748171

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Authors
Zhang, X., Zhang, Y., He, Z., Yin, K., Li, B., Zhang, L., & Xu, Z.
Affiliations
  • Affiliated Hospital of Xuzhou Medical College (CN)
  • Nanjing University of Chinese Medicine (CN)
  • Jiangsu Province Hospital (CN)
  • Affiliated Hospital of Jiangsu University (CN)
Corresponding author
Xu, Zekuan
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2019-10-17
Volume
10
Issue
11
Pages
788-788
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-019-2030-2
PMC
PMC6797812
OpenAlex
W2981115917
Cited by
261
References
46
Citations by year
2026: 43 · 2025: 48 · 2024: 32 · 2023: 34 · 2022: 55 · 2021: 32 · 2020: 16
FWCI
20.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (JX10231801, 81272712, 81572362, 20181119, BRA2015474, 81602080, 81272712, 81572362)
  • Government of Jiangsu Province (333 Project)
  • Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD, JX10231801, JX 10231801, 81572362, BRA2015474)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords
chronic stress, gastric cancer, ADRB2, beta2-adrenergic receptor, adrenergic signaling, tumor progression, metastasis, chronic restraint stress, catecholamines, cortisol, propranolol, atenolol, NF-κB, STAT3, vascular endothelial growth factor, matrix metalloproteinases, cell proliferation, cell invasion
MeSH terms
Animals, Cell Movement, Female, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasm Metastasis, RNA, Messenger, Stomach Neoplasms, Stress, Physiological, Signal Transduction, NF-kappa B, Receptors, Adrenergic, beta-2, Disease Progression, MAP Kinase Signaling System, Cell Proliferation, STAT3 Transcription Factor, Mice, Heterografts

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