Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling.

Abstract

Although it is established that the sustained psychologic stress conditions under which patients with tumors often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychologic stress on tumor progression was verified using a stress-stimulated tumor-bearing mouse model (Str-tumor). Both D2 dopamine receptor (DRD2) and hypoxia-inducible factor-1α (HIF1α) were highly expressed in the nucleus of Str-tumors. Treatment with trifluoperazine (TFP), a DRD2 inhibitor, elicited better antitumor effects in Str-tumors than the control group. These results indicate that DRD2 may mediate stress-induced malignant tumor progression. DRD2 interacted with von Hippel-Lindau (VHL) in the nucleus, and competitive binding of DRD2 and HIF1α to VHL resulted in reduced ubiquitination-mediated degradation of HIF1α, enhancing the epithelial-mesenchymal transition of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF1α. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychologic stress via activation of the oxygen-independent HIF1α pathway, and TFP may serve as a therapeutic strategy for stress management in patients with cancer. SIGNIFICANCE: This work identifies DRD2 regulation of HIF1α as a mechanism underlying the progression of malignant tumors stimulated by psychologic stress and suggests that DRD2 inhibition can mitigate these stress conditions in patients.See related commentary by Bernabé, p. 5144.

• Authors: Huijuan Liu, Jiahuan Yang, Yang Zhang, Jingxia Han, Yuyan Yang, Zihan Zhao, Xintong Dai, Hongqi Wang, Xiujuan Ding, Yanrong Liu, Weilong Zhong, Wenqing Gao, Tao Sun
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 20 Pg. 5353-5365 (10 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34321238 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• DRD2 protein, mouse
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, Dopamine D2
• Von Hippel-Lindau Tumor Suppressor Protein
• VHL protein, mouse

Topics

• Animals
• Apoptosis
• Binding, Competitive
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Melanoma, Experimental (etiology, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Receptors, Dopamine D2 (genetics, metabolism)
• Stress, Psychological (complications)
• Tumor Cells, Cultured
• Ubiquitination
• Von Hippel-Lindau Tumor Suppressor Protein (genetics, metabolism)