Gámez-García Andrés, Bolinaga-Ayala Idoia, Yoldi Guillermo, Espinosa-Gil Sergio, Diéguez-Martínez Nora, Megías-Roda Elisabet, Muñoz-Guardiola Pau, Lizcano Jose M
Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
Protein Kinases in Cancer Research, Vall Hebron Institut de Recerca (VHIR), Barcelona, Spain.
Front Cell Dev Biol. 2021 Nov 4;9:742049. doi: 10.3389/fcell.2021.742049. eCollection 2021.
Autophagy is a highly conserved intracellular process that preserves cellular homeostasis by mediating the lysosomal degradation of virtually any component of the cytoplasm. Autophagy is a key instrument of cellular response to several stresses, including endoplasmic reticulum (ER) stress. Cancer cells have developed high dependency on autophagy to overcome the hostile tumor microenvironment. Thus, pharmacological activation or inhibition of autophagy is emerging as a novel antitumor strategy. ERK5 is a novel member of the MAP kinase family that is activated in response to growth factors and different forms of stress. Recent work has pointed ERK5 as a major player controlling cancer cell proliferation and survival. Therefore small-molecule inhibitors of ERK5 have shown promising therapeutic potential in different cancer models. Here, we report for the first time ERK5 as a negative regulator of autophagy. Thus, ERK5 inhibition or silencing induced autophagy in a panel of human cancer cell lines with different mutation patterns. As reported previously, ERK5 inhibitors (ERK5i) induced apoptotic cancer cell death. Importantly, we found that autophagy mediates the cytotoxic effect of ERK5i, since -- autophagy-deficient cells viability was not affected by these compounds. Mechanistically, ERK5i stimulated autophagic flux independently of the canonical regulators AMPK or mTORC1. Moreover, ERK5 inhibition resulted in ER stress and activation of the Unfolded Protein Response (UPR) pathways. Specifically, ERK5i induced expression of the ER luminal chaperone BiP (a hallmark of ER stress), the UPR markers CHOP and ATF4, and the spliced form of XBP1. Pharmacological inhibition of UPR with chemical chaperone TUDC, or ATF4 silencing, resulted in impaired ERK5i-mediated UPR, autophagy and cytotoxicity. Overall, our results suggest that ERK5 inhibition induces autophagy-mediated cancer cell death by activating ER stress. Since ERK5 inhibition sensitizes cancer cells and tumors to chemotherapy, future work will determine the relevance of UPR and autophagy in the combined use of chemotherapy and ERK5i to tackle Cancer.
自噬是一种高度保守的细胞内过程，通过介导细胞质中几乎任何成分的溶酶体降解来维持细胞内稳态。自噬是细胞对多种应激（包括内质网（ER）应激）作出反应的关键机制。癌细胞高度依赖自噬来克服恶劣的肿瘤微环境。因此，自噬的药理学激活或抑制正成为一种新型抗肿瘤策略。ERK5是丝裂原活化蛋白激酶（MAP）家族的新成员，可响应生长因子和不同形式的应激而被激活。最近的研究表明，ERK5是控制癌细胞增殖和存活的主要因子。因此，ERK5小分子抑制剂在不同癌症模型中显示出有前景的治疗潜力。在此，我们首次报道ERK5是自噬的负调节因子。因此，ERK5抑制或沉默在一组具有不同突变模式的人类癌细胞系中诱导了自噬。如先前报道，ERK5抑制剂（ERK5i）可诱导癌细胞凋亡性死亡。重要的是，我们发现自噬介导了ERK5i的细胞毒性作用，因为自噬缺陷细胞的活力不受这些化合物的影响。从机制上讲，ERK5i独立于经典调节因子AMPK或mTORC1刺激自噬流。此外，ERK5抑制导致内质网应激和未折叠蛋白反应（UPR）途径的激活。具体而言，ERK5i诱导内质网腔伴侣BiP（内质网应激的标志）、UPR标志物CHOP和ATF4以及XBP1的剪接形式的表达。用化学伴侣TUDC对UPR进行药理学抑制或ATF4沉默，会导致ERK5i介导的UPR、自噬和细胞毒性受损。总体而言，我们的结果表明，ERK5抑制通过激活内质网应激诱导自噬介导的癌细胞死亡。由于ERK5抑制使癌细胞和肿瘤对化疗敏感，未来的研究将确定UPR和自噬在联合使用化疗和ERK5i治疗癌症中的相关性。
