Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Mol Cancer Res. 2023 Dec 1;21(12):1288-1302. doi: 10.1158/1541-7786.MCR-22-0871.
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 and in vivo in 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/suppression status-quo is 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.
Altogether, β-arrestin system bias downstream IGF1R is an important metastatic melanoma vulnerability that may be conductive for therapeutic benefit.
长期以来，p53 肿瘤抑制途径的限制一直与黑色素瘤的进展、治疗耐药性和预后不良有关，黑色素瘤是最具侵袭性的皮肤癌。同样，胰岛素样生长因子 1 型受体（IGF1R）被认为是黑色素瘤细胞转化、增殖、存活和迁移的重要协调因子。鉴于β-arrestin（β-arr）系统通过其共同的 E3 泛素蛋白连接酶 MDM2 严格控制抗/肿瘤发生的 p53/IGF1R 信号通路，我们探讨了是否可以通过改变 IGF1R 下游的β-arr 系统来增强黑色素瘤细胞对化疗的反应。改变β-arr 的表达表明，β-arr1 沉默和β-arr2 过表达（-β-arr1/+β-arr2）都促进了 MDM2 从核到细胞质的易位，伴随着 IGF1R 表达的降低，同时增加了 p53 水平，从而降低了细胞的增殖/存活。β-arr2 的不平衡（-β-arr1/+β-arr2）与化疗药物达卡巴嗪协同作用，促进黑色素瘤细胞毒性。在 3D 球体模型和斑马鱼体内模型中，通过双重 IGF1R 下调/p53 激活，这种联合策略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-arr1-/β-arr2+失衡是一种转移性黑色素瘤的脆弱性，可能增强治疗效果。我们的研究结果表明，在稳定状态下，β-arr1/2 平衡维持了 IGF1R/p53-促进肿瘤生长/抑制肿瘤的状态。使这种平衡向β-arr2 倾斜可以限制 IGF1R 的促肿瘤活性，同时增强 p53 的活性，从而减少多种维持癌症的机制。与其他治疗方法联合使用，这种策略可以提高患者对依赖 p53 或 IGF1R 途径的治疗的反应和效果。
总的来说，β-arrestin 系统下游 IGF1R 的偏向是一个重要的转移性黑色素瘤的脆弱性，可能有利于治疗效果。
