Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling.
Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling.
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心理压力通过 DRD2/HIF1α 信号传导促进恶性肿瘤进展
DOI：
10.1158/0008-5472.can-21-1043
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
本研究确定DRD2调控HIF1α是恶性肿瘤在心理应激刺激下发展的一种机制，并表明抑制DRD2可以减轻患者的这些应激条件。虽然已经确定肿瘤患者经常处于的持续的心理应激状态会加速肿瘤的恶性进展，但这种关联背后的分子机制尚不清楚。在这项工作中，通过应激刺激荷瘤小鼠模型（Str-tumor）验证了心理应激对肿瘤进展的影响。D2多巴胺受体（DRD2）和缺氧诱导因子-1α (HIF1α)在str -肿瘤细胞核中高表达。用DRD2抑制剂三氟拉嗪（TFP）治疗str -肿瘤比对照组有更好的抗肿瘤效果。这些结果表明DRD2可能介导应激诱导的恶性肿瘤进展。DRD2在细胞核中与von Hippel-Lindau （VHL）相互作用，DRD2和HIF1α与VHL的竞争性结合导致泛素化介导的HIF1α降解减少，增强肿瘤细胞的上皮-间质转化。TFP作为DRD2和VHL之间的界面抑制剂，促进HIF1α的降解。综上所述，DRD2可能通过激活氧非依赖性HIF1α通路促进心理应激诱导的恶性肿瘤的进展，TFP可能作为癌症患者压力管理的一种治疗策略。本研究确定了DRD2调控HIF1α是恶性肿瘤在心理应激刺激下发展的机制，并表明抑制DRD2可以减轻患者的这些应激条件。参见bernab<e:1>的相关评论，
This work identifies DRD2 regulation of HIF1α as a mechanism underlying the progression of malignant tumors stimulated by psychological stress and suggests that DRD2 inhibition can mitigate these stress conditions in patients. 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. 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,
影响因子：
37.3
作者：
Arranz A;Venihaki M;Mol B;Androulidaki A;Dermitzaki E;Rassouli O;Ripoll J;Stathopoulos EN;Gomariz RP;Margioris AN;Tsatsanis C
通讯作者：
Tsatsanis C
影响因子：
3.7
作者：
Fatakia SN;Costanzi S;Chow CC
通讯作者：
Chow CC
影响因子：
8.8
作者：
Rofstad EK;Danielsen T
通讯作者：
Danielsen T