Abstract
TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis selectively in cancer cells. For melanoma, the targeting of TRAIL signaling appears highly attractive, due to pronounced TRAIL receptor expression in tumor tissue. However, mechanisms of TRAIL resistance observed in melanoma cells may limit its clinical use. The Bcl-2 family members are critical regulators of cell-intrinsic apoptotic pathways. Thus, the antiapoptotic Bcl-2 protein myeloid cell leukemia 1 (Mcl-1) is overexpressed in many tumor types and was linked to chemotherapy resistance in melanoma. In this study, we evaluated the involvement of antiapoptotic Bcl-2 proteins (Bcl-2, Bcl-xL , Bcl-w, Mcl-1, Bcl-A1, and Bcl-B) in TRAIL resistance. They were targeted by small interfering RNA-mediated silencing in TRAIL-sensitive (A-375, Mel-HO) and in TRAIL-resistant melanoma cell lines (Mel-2a, MeWo). This highlighted Mcl-1 as the most efficient target to overcome TRAIL resistance. In this context, we investigated the effects of Mcl-1-targeting microRNAs as well as the Mcl-1-selective inhibitor S63845. Both miR-193b and S63845 resulted in significant enhancement of TRAIL-induced apoptosis, associated with decreased cell viability. Apoptosis induction was mediated by caspase-3 processing as well as by Bax and Bak activation, indicating the critical involvement of intrinsic apoptosis pathways. These data may indicate a high relevance of Mcl-1 targeting also in melanoma therapy. Furthermore, the data may suggest to consider the use of the tumor suppressor miR-193b as a strategy for countering TRAIL resistance in melanoma.
Highlights
Selective inhibitors for the mitogen‐activated protein (MAP) kinases BRAF and MAP kinase‐ERK kinase, as well as immune checkpoint modulators, have significantly improved melanoma therapy in recent years, demonstrating the high potential of targeted strategies in cancer.[1,2,3] melanoma remains the major cause of skin cancer‐related deaths.[3]
We evaluated the involvement of antiapoptotic Bcl‐2 proteins (Bcl‐2, Bcl‐xL, Bcl‐w, myeloid cell leukemia 1 (Mcl‐1), Bcl‐A1, and Bcl‐B) in TNF‐related apoptosis‐inducing ligand (TRAIL) resistance
We investigated the effects of knockdown of antiapoptotic Bcl‐2 proteins with regard to the sensitization of melanoma cells for TRAIL‐induced apoptosis
Summary
Selective inhibitors for the mitogen‐activated protein (MAP) kinases BRAF and MAP kinase‐ERK kinase, as well as immune checkpoint modulators, have significantly improved melanoma therapy in recent years, demonstrating the high potential of targeted strategies in cancer.[1,2,3] melanoma remains the major cause of skin cancer‐related deaths.[3]. A particular advantage of TRAIL is selective apoptosis induction in cancer cells, while normal tissue cells are largely spared.[13,14] melanoma cells have been shown to constitutively express DR5, this does not guarantee TRAIL sensitivity, as roughly half of melanoma cell lines reveal an intrinsic TRAIL resistance.[15,16] To address this limitation, different combination strategies have been identified, which can sensitize melanoma cells for TRAIL‐induced apoptosis In this context, the control of mitochondrial apoptosis pathways came into particular focus for explaining TRAIL resistance in melanoma.[17,18]. We further investigated and compared different Mcl‐1 targeting strategies as the selective inhibitor S63845, miR‐193b, and miR‐339‐3p to overcome TRAIL resistance in melanoma cells
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