Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid 28029, Spain.
Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca 37007, Spain.
Biochem Pharmacol. 2021 Nov;193:114810. doi: 10.1016/j.bcp.2021.114810. Epub 2021 Oct 19.
A shared characteristic of many tumors is the lack of response to anticancer drugs. Multiple mechanisms of pharmacoresistance (MPRs) are involved in permitting cancer cells to overcome the effect of these agents. Pharmacoresistance can be primary (intrinsic) or secondary (acquired), i.e., triggered or enhanced in response to the treatment. Moreover, MPRs usually result in the lack of sensitivity to several agents, which accounts for diverse multidrug-resistant (MDR) phenotypes. MPRs are based on the dynamic expression of more than one hundred genes, constituting the so-called resistome. Alternative splicing (AS) during pre-mRNA maturation results in changes affecting proteins involved in the resistome. The resulting splicing variants (SVs) reduce the efficacy of anticancer drugs by lowering the intracellular levels of active agents, altering molecular targets, enhancing both DNA repair ability and defensive mechanism of tumors, inducing changes in the balance between pro-survival and pro-apoptosis signals, modifying interactions with the tumor microenvironment, and favoring malignant phenotypic transitions. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the impact of AS on MPR in cancer cells.
许多肿瘤的一个共同特征是缺乏对抗癌药物的反应。多种药物耐药机制（MPRs）参与允许癌细胞克服这些药物的作用。药物耐药性可以是原发性（内在）或继发性（获得性）的，即对治疗的反应而引发或增强。此外，MPRs 通常导致对几种药物缺乏敏感性，这解释了多种多药耐药（MDR）表型。MPRs 基于超过一百个基因的动态表达，构成所谓的耐药组。在 pre-mRNA 成熟过程中的选择性剪接（AS）导致影响耐药组中涉及的蛋白质的变化。由此产生的剪接变体（SVs）通过降低细胞内活性药物的水平、改变分子靶标、增强 DNA 修复能力和肿瘤防御机制、诱导促生存和促凋亡信号之间平衡的变化、修饰与肿瘤微环境的相互作用以及促进恶性表型转变来降低抗癌药物的疗效。导致与癌症相关的异常剪接的原因包括创建或破坏剪接位点或剪接增强子或沉默子的突变、剪接因子的异常表达以及影响剪接机制活性的信号通路受损。在这里，我们回顾了 AS 对癌细胞中 MPR 的影响。
