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Psychological stress drives progression of malignant tumors via DRD2/HIF-1α signaling.

Cancer Research 2021 July 29
Although it is established that the sustained psychological stress conditions under which tumor patients often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychological 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 1-alpha (HIF-1α) were highly expressed in the nucleus of stress-stimulated 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 HIF-1α to VHL resulted in reduced ubiquitination-mediated degradation of HIF-1α, enhancing the epithelial-mesenchymal transition (EMT) of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF-1α. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychological stress via activation of the oxygen-independent HIF-1α pathway, and TFP may serve as a therapeutic strategy for stress management in cancer patients.

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