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

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-1 alpha (HIF1 alpha) 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 HIF1 alpha to VHL resulted in reduced ubiquitination-mediated degradation of HIF1 alpha, enhancing the epithelial-mesenchymal transition of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF1 alpha. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychologic stress via activation of the oxygen-independent HIF1 alpha pathway, and TFP may serve as a therapeutic strategy for stress management in patients with cancer. Significance: This work identifies DRD2 regulation of HIF1 alpha 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.

Automated summary

This study confirmed the impact of psychological stress on tumor progression and identified DRD2 as a potential mediator of stress-induced malignant tumor progression. The results suggest that DRD2 regulation of HIF1 alpha may play a key role in this process, and DRD2 inhibition with TFP could be a promising therapeutic strategy for managing stress in cancer patients.