Bcl-xL: A Focus on Melanoma Pathobiology

Abstract

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.

Keywords: Bcl-xL; apoptosis; cancer; invasion; melanoma; migration.

Figure 1

Schematic representation of the anti-apoptotic Bcl-2 family members. Bcl-2 homology (BH) and transmembrane domains are represented in distinct colours. The hydrophobic pocket is marked in grey.

Figure 2

Schematic representation of the alternative spliced variants Bcl-xL, Bcl-xS and Bcl-xβ. Bcl-2 homology (BH) and transmembrane domains are represented in green. Alternative sequence present in Bcl-x(Beta)(Bcl-xβ) is reported in violet. No defined domains are shown in pink.

Figure 3

Transcriptional factors and effectors involved in the Bcl-xL regulation.

Figure 4

Non-canonical role played by Bcl-xL on melanoma. Bcl-xL is involved in metastasis, angiogenesis, chemoresistance against different chemotherapeutic drugs, and autophagy.