Competing Engagement of β-arrestin Isoforms Balances IGF1R/p53 Signaling and Controls Melanoma Cell Chemotherapeutic Responsiveness.
Competing Engagement of β-arrestin Isoforms Balances IGF1R/p53 Signaling and Controls Melanoma Cell Chemotherapeutic Responsiveness.
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β-抑制蛋白亚型的竞争性参与平衡 IGF1R/p53 信号传导并控制黑色素瘤细胞化疗反应。
DOI：
10.1158/1541-7786.mcr-22-0871
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Girnita,Leonard
中科院分区：
文献类型：
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作者：
Cismas,Sonia;Pasca,Sylvya;Crudden,Caitrin;TrocoliDrakensjo,Iara;Suleymanova,Naida;Zhang,Simin;Gebhard,Benjamin;Song,Dawei;Neo,Shiyong;Shibano,Takashi;Smith,TerryJ;Calin,GeorgeA;Girnita,Ada;Girnita,Leonard
长期以来，对p53肿瘤抑制途径的限制与黑色素瘤（最具侵袭性的皮肤癌形式）的进展、治疗抗性和预后不良有关。同样，胰岛素样生长因子1型受体（IGF 1 R）被认为是黑色素瘤细胞转化、增殖、存活和迁移的重要协调者。鉴于β-抑制蛋白（β-arrestin，β-ARRESTIN）系统通过其共同的E3泛素-蛋白连接酶MDM 2控制抗/促肿瘤p53/IGF 1 R信号通路，我们探讨IGF 1 R下游的该系统失衡是否可以增强黑素瘤细胞对化疗的反应。改变β-arr 1表达表明，β-arr 1沉默和β-arr 2过表达（-β-arr 1/+β-arr 2）均促进了MDM 2的核-胞浆易位，同时伴有IGF 1 R表达降低，同时增加了p53水平，导致细胞增殖/存活降低。向β-arr 2的不平衡（-β-arr 1/+β-arr 2）与化疗剂达卡巴嗪协同促进黑素瘤细胞毒性。在3D球体模型和体内斑马鱼模型中，这种联合策略通过双重IGF 1 R下调/p53激活，限制了黑色素瘤细胞的生长、存活和转移扩散。在临床环境中，对TCGA-SKCM患者队列的分析证实β-arr 1 −/β-arr 2+失衡是转移性黑色素瘤的易感性，可能会增强治疗获益。我们的研究结果表明，在稳态条件下，β-arr 1/2稳态维持了IGF 1 R/p53-肿瘤促进/抑制状态。使这种平衡偏向β-arr 2可以限制促肿瘤性IGF 1 R活性，同时增强p53活性，从而减少多种癌症维持机制。与其他疗法相结合，这种策略改善了患者对依赖于p53或IGF 1 R途径的疗法的反应和结果。
Constraints on the p53 tumor suppressor pathway have long been associated with the progression, therapeutic resistance, and poor prognosis of melanoma, the most aggressive form of skin cancer. Likewise, the insulin-like growth factor type 1 receptor (IGF1R) is recognized as an essential coordinator of transformation, proliferation, survival, and migration of melanoma cells. Given that β-arrestin (β-arr) system critically governs the anti/pro-tumorigenic p53/IGF1R signaling pathways through their common E3 ubiquitin-protein ligase MDM2, we explore whether unbalancing this system downstream of IGF1R can enhance the response of melanoma cells to chemotherapy. Altering β-arr expression demonstrated that both β-arr1-silencing and β-arr2-overexpression (-β-arr1/+β-arr2) facilitated nuclear-to-cytosolic MDM2 translocation accompanied by decreased IGF1R expression, while increasing p53 levels, resulting in reduced cell proliferation/survival. Imbalance towards β-arr2 (-β-arr1/+β-arr2) synergizes with the chemotherapeutic agent, dacarbazine, in promoting melanoma cell toxicity. In both 3D spheroid models andin vivoin zebrafish models, this combination strategy, through dual IGF1R downregulation/p53 activation, limits melanoma cell growth, survival and metastatic spread. In clinical settings, analysis of the TCGA-SKCM patient cohort confirms β-arr1−/β-arr2+imbalance as a metastatic melanoma vulnerability that may enhance therapeutic benefit. Our findings suggest that under steady-state conditions, IGF1R/p53-tumor promotion/suppressionstatus-quois preserved by β-arr1/2 homeostasis. Biasing this balance towards β-arr2 can limit the protumorigenic IGF1R activities while enhancing p53 activity, thus reducing multiple cancer-sustaining mechanisms. Combined with other therapeutics, this strategy improves patient responses and outcomes to therapies relying on p53 or IGF1R pathways.ImplicationsAltogether, β-arrestin system bias downstream IGF1R is an important metastatic melanoma vulnerability that may be conductive for therapeutic benefit.