Departament de Bioquímica i Biologia Molecular, Unitat de Medicina, and Institut de Neurociències, Universitat Autònoma de Barcelona (UAB), 08193, Barcelona, Spain.
Protein Kinases in Cancer Research, Vall Hebron Institut de Recerca (VHIR), Edifici Collserola, Laboratory 143, Passeig de la Vall d'Hebron, 119-129, 08035, Barcelona, Spain.
Cell Mol Life Sci. 2022 Sep 19;79(10):524. doi: 10.1007/s00018-022-04541-6.
Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.
子宫内膜癌（EC）是发达国家女性最常见的妇科癌症类型。尽管手术联合化疗/放疗方案，高危 EC 肿瘤患者的总体生存率仍然很差，这表明需要新的治疗方法。MEK5-ERK5 通路在生长因子和不同应激源（包括氧化应激和细胞因子）的刺激下被激活。先前的证据支持 MEK5-ERK5 通路在几种癌症的病理学中发挥作用。我们研究了 ERK5 在 EC 中的作用。PanCancer Atlas 数据集的计算机分析显示，48%的 EC 患者存在 MEK5-ERK5 通路成分的改变。在这里，我们显示 ERK5 抑制或沉默降低了 EGF 诱导的 EC 细胞增殖，并且 MEK5 的基因缺失导致 EC 增殖受损，并在裸鼠中降低了肿瘤生长能力。药物抑制或 ERK5 沉默可损害 EC 细胞和异种移植物中的 NF-kB 通路。此外，我们在人 EC 肿瘤样本中发现 ERK5 与 p65/RELA 蛋白水平之间存在正相关。从机制上讲，ERK5 的遗传或药物损伤导致 NEMO/IKKγ 表达下调，导致 p65/RELA 活性受损，并导致 EC 细胞和异种移植物凋亡，而 NEMO/IKKγ 的过表达可挽救这一现象。值得注意的是，ERK5 抑制、MEK5 缺失或 NF-kB 抑制可使 EC 细胞对标准 EC 化疗（紫杉醇/卡铂）毒性敏感，而 ERK5 抑制与紫杉醇协同作用可减少小鼠肿瘤异种移植物的生长。总之，我们的结果表明 ERK5-NEMO-NF-κB 通路介导了 EC 细胞的增殖和存活。我们提出 ERK5/NF-κB 轴作为 EC 治疗的新靶点。
