Eberhardt Wolfgang, Nasrullah Usman, Pfeilschifter Josef
Institute of General Pharmacology and Toxicology, Goethe University Frankfurt, 60590 Frankfurt, Germany.
Cells. 2025 Jan 7;14(2):65. doi: 10.3390/cells14020065.
Therapy resistance still constitutes a common hurdle in the treatment of many human cancers and is a major reason for treatment failure and patient relapse, concomitantly with a dismal prognosis. In addition to "intrinsic resistance", e.g., acquired by random mutations, cancer cells typically escape from certain treatments ("acquired resistance") by a large variety of means, including suppression of apoptosis and other cell death pathways via upregulation of anti-apoptotic factors or through inhibition of tumor-suppressive proteins. Therefore, ideally, the tumor-cell-restricted induction of apoptosis is still considered a promising avenue for the development of novel, tumor (re)sensitizing therapies. A growing body of evidence has highlighted the multifaceted role of tripartite motif 25 (TRIM25) in controlling different aspects of tumorigenesis, including chemotherapeutic drug resistance. Accordingly, overexpression of TRIM25 is observed in many tumors and frequently correlates with a poor patient survival. In addition to its originally described function in antiviral innate immune response, TRIM25 can play critical yet context-dependent roles in apoptotic- and non-apoptotic-regulated cell death pathways, including pyroposis, necroptosis, ferroptosis, and autophagy. The review summarizes current knowledge of molecular mechanisms by which TRIM25 can interfere with different cell death modalities and thereby affect the success of currently used chemotherapeutics. A better understanding of the complex repertoire of cell death modulatory effects by TRIM25 is an essential prerequisite for validating TRIM25 as a potential target for future anticancer therapy to surmount the high failure rate of currently used chemotherapies.
治疗耐药性仍然是许多人类癌症治疗中常见的障碍，是治疗失败和患者复发的主要原因，同时预后也很糟糕。除了“内在耐药性”，例如通过随机突变获得的耐药性外，癌细胞通常还会通过多种方式逃避某些治疗（“获得性耐药”），包括通过上调抗凋亡因子或抑制肿瘤抑制蛋白来抑制凋亡和其他细胞死亡途径。因此，理想情况下，肿瘤细胞特异性诱导凋亡仍被认为是开发新型肿瘤（再）致敏疗法的有前景的途径。越来越多的证据强调了三联基序蛋白25（TRIM25）在控制肿瘤发生的不同方面，包括化疗耐药性方面的多方面作用。相应地，在许多肿瘤中观察到TRIM25的过表达，并且经常与患者的不良生存相关。除了其最初描述的在抗病毒先天免疫反应中的功能外，TRIM25在凋亡和非凋亡调节的细胞死亡途径中，包括细胞焦亡、坏死性凋亡、铁死亡和自噬中，可以发挥关键但依赖于背景的作用。本综述总结了目前关于TRIM25干扰不同细胞死亡方式从而影响当前使用的化疗药物疗效的分子机制的知识。更好地理解TRIM25对细胞死亡调节作用的复杂情况，是将TRIM25验证为未来抗癌治疗的潜在靶点以克服当前使用的化疗高失败率的必要前提。
