Departamento de Biología Celular e Histología, Facultad de Biología, Universidad de Murcia, IMIB-Arrixaca, Centro de Investigación Biomédica en Red de Enfermedades Raras, 30100 Murcia, Spain.
Preclinical Models and New Therapeutic Agents Unit, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.
Int J Mol Sci. 2021 Mar 9;22(5):2777. doi: 10.3390/ijms22052777.
Apoptosis is the main mechanism by which multicellular organisms eliminate damaged or unwanted cells. To regulate this process, a balance between pro-survival and pro-apoptotic proteins is necessary in order to avoid impaired apoptosis, which is the cause of several pathologies, including cancer. Among the anti-apoptotic proteins, Bcl-xL exhibits a high conformational flexibility, whose regulation is strictly controlled by alternative splicing and post-transcriptional regulation mediated by transcription factors or microRNAs. It shows relevant functions in different forms of cancer, including melanoma. In melanoma, Bcl-xL contributes to both canonical roles, such as pro-survival, protection from apoptosis and induction of drug resistance, and non-canonical functions, including promotion of cell migration and invasion, and angiogenesis. Growing evidence indicates that Bcl-xL inhibition can be helpful for cancer patients, but at present, effective and safe therapies targeting Bcl-xL are lacking due to toxicity to platelets. In this review, we summarized findings describing the mechanisms of Bcl-xL regulation, and the role that Bcl-xL plays in melanoma pathobiology and response to therapy. From these findings, it emerged that even if Bcl-xL plays a crucial role in melanoma pathobiology, we need further studies aimed at evaluating the involvement of Bcl-xL and other members of the Bcl-2 family in the progression of melanoma and at identifying new non-toxic Bcl-xL inhibitors.
细胞凋亡是多细胞生物消除受损或不需要的细胞的主要机制。为了调节这个过程，需要在生存促进蛋白和促凋亡蛋白之间保持平衡，以避免凋亡受损，这是包括癌症在内的几种病理学的原因。在抗凋亡蛋白中，Bcl-xL 表现出高度的构象灵活性，其调节受到替代性剪接和转录因子或 microRNAs 介导的转录后调节的严格控制。它在不同形式的癌症中表现出相关功能，包括黑色素瘤。在黑色素瘤中，Bcl-xL 有助于两种典型作用，如生存促进、保护免受凋亡和诱导耐药性，以及非典型作用，包括促进细胞迁移和侵袭以及血管生成。越来越多的证据表明，Bcl-xL 抑制可能对癌症患者有帮助，但目前由于对血小板的毒性，缺乏针对 Bcl-xL 的有效和安全的治疗方法。在这篇综述中，我们总结了描述 Bcl-xL 调节机制的研究结果，以及 Bcl-xL 在黑色素瘤发病机制和对治疗的反应中的作用。从这些发现中可以看出，即使 Bcl-xL 在黑色素瘤发病机制中起着至关重要的作用，我们仍需要进一步的研究，以评估 Bcl-xL 及 Bcl-2 家族的其他成员在黑色素瘤进展中的参与情况，并确定新的非毒性 Bcl-xL 抑制剂。
