Vietri Mariapia, Miranda Maria Rosaria, Amodio Giuseppina, Ciaglia Tania, Bertamino Alessia, Campiglia Pietro, Remondelli Paolo, Vestuto Vincenzo, Moltedo Ornella
Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084 Fisciano, SA, Italy.
Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana"/DIPMED, Via S. Allende, 84081 Baronissi, SA, Italy.
Biomolecules. 2025 Jun 25;15(7):930. doi: 10.3390/biom15070930.
Lysosomal dysfunction and endoplasmic reticulum (ER) stress play essential roles in cancer cell survival, growth, and stress adaptation. Among the various stressors in the tumor microenvironment, oxidative stress (OS) is a central driver that exacerbates both lysosomal and ER dysfunction. In healthy cells, the ER manages protein folding and redox balance, while lysosomes regulate autophagy and degradation. Cancer cells, however, are frequently exposed to elevated levels of reactive oxygen species (ROS), which disrupt protein folding in the ER and damage lysosomal membranes and enzymes, promoting dysfunction. Persistent OS activates the unfolded protein response (UPR) and contributes to lysosomal membrane permeabilization (LMP), leading to pro-survival autophagy or cell death depending on the context and on the modulation of pathways like PERK, IRE1, and ATF6. Cancer cells exploit these pathways by enhancing their tolerance to OS and shifting UPR signaling toward survival. Moreover, lysosomal impairment due to ROS accumulation compromises autophagy, resulting in the buildup of damaged organelles and further amplifying oxidative damage. This vicious cycle of ROS-induced ER stress and lysosomal dysfunction contributes to tumor progression, therapy resistance, and metabolic adaptation. Thus, targeting lysosomal and ER stress responses offers potential as cancer therapy, particularly in increasing oxidative stress and promoting apoptosis. This review explores the interconnected roles of lysosomal dysfunction, ER stress, and OS in cancer, focusing on the mechanisms driving their crosstalk and its implications for tumor progression and therapeutic resistance.
溶酶体功能障碍和内质网（ER）应激在癌细胞的存活、生长和应激适应中起着至关重要的作用。在肿瘤微环境中的各种应激源中，氧化应激（OS）是加剧溶酶体和内质网功能障碍的核心驱动因素。在健康细胞中，内质网负责蛋白质折叠和氧化还原平衡，而溶酶体调节自噬和降解。然而，癌细胞经常暴露于高水平的活性氧（ROS）中，这会破坏内质网中的蛋白质折叠，损害溶酶体膜和酶，从而促进功能障碍。持续的氧化应激激活未折叠蛋白反应（UPR），并导致溶酶体膜通透性增加（LMP），根据具体情况以及PERK、IRE1和ATF6等信号通路的调节，导致促生存自噬或细胞死亡。癌细胞通过增强对氧化应激的耐受性并将未折叠蛋白反应信号转向生存来利用这些信号通路。此外，由于ROS积累导致的溶酶体损伤会损害自噬，导致受损细胞器的积累，并进一步放大氧化损伤。ROS诱导的内质网应激和溶酶体功能障碍的这种恶性循环促进了肿瘤进展、治疗抵抗和代谢适应。因此，针对溶酶体和内质网应激反应具有作为癌症治疗方法的潜力，特别是在增加氧化应激和促进细胞凋亡方面。本综述探讨了溶酶体功能障碍、内质网应激和氧化应激在癌症中的相互关联作用，重点关注驱动它们相互作用的机制及其对肿瘤进展和治疗抵抗的影响。
