title: Selective induction of cell death in melanoma cell lines through targeting of Mcl-1 and A1.
abstract: Melanoma is an often fatal form of skin cancer which is remarkably resistant against radio- and chemotherapy. Even new strategies that target RAS/RAF signaling and display unprecedented efficacy are characterized by resistance mechanisms. The targeting of survival pathways would be an attractive alternative strategy, if tumor-specific cell death can be achieved. Bcl-2 proteins play a central role in regulating survival of tumor cells. In this study, we systematically investigated the relevance of antiapoptotic Bcl-2 proteins, i.e., Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and A1, in melanoma cell lines and non-malignant cells using RNAi. We found that melanoma cells required the presence of specific antiapoptotic Bcl-2 proteins: Inhibition of Mcl-1 and A1 strongly induced cell death in some melanoma cell lines, whereas non-malignant cells, i.e., primary human fibroblasts or keratinocytes were not affected. This specific sensitivity of melanoma cells was further enhanced by the combined inhibition of Mcl-1 and A1 and resulted in 60% to 80% cell death in all melanoma cell lines tested. This treatment was successfully combined with chemotherapy, which killed a substantial proportion of cells that survived Mcl-1 and A1 inhibition. Together, these results identify antiapoptotic proteins on which specifically melanoma cells rely on and, thus, provide a basis for the development of new Bcl-2 protein-targeting therapies.
authors.affiliation: Department of Dermatology and Allergology, Ludwig-Maximilian University, Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Senft
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.forename: Saskia A
authors.initials: SA
authors.lastname: Graf
authors.forename: Claudia
authors.initials: C
authors.lastname: Kammerbauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy / Q000379:methods*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D061251:Primary Cell Culture; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D012867:Skin / Q000166:cytology / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D013379:Substrate Specificity / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering