The combination of TPL2 knockdown and TNFα causes synthetic lethality via caspase-8 activation in human carcinoma cell lines

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-07, Vol.116 (28), p.14039-14048
• Main Authors: Serebrennikova, Oksana B., Paraskevopoulou, Maria D., Aguado-Fraile, Elia, Taraslia, Vasiliki, Ren, Wenying, Thapa, Geeta, Roper, Jatin, Du, Keyong, Croce, Carlo M., Tsichlis, Philip N.
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - genetics; Biological Sciences; Biotechnology; c-FLIP protein; Carcinoma - drug therapy; Carcinoma - genetics; Carcinoma - pathology; Caspase; Caspase 8 - genetics; Caspase Inhibitors - pharmacology; Caspase-8; Cell activation; Clustering; Drug Resistance, Neoplasm - genetics; Feasibility studies; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; HeLa Cells; Humans; Kinases; Lethality; Macrophages - metabolism; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; MicroRNAs - genetics; Phenotypes; Phosphorylation - drug effects; PNAS Plus; Protein kinase; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; RNA, Small Interfering - genetics; Signal Transduction; siRNA; Synthetic Lethal Mutations - genetics; Threonine; Tumor cell lines; Tumor cells; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-α; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1901465116

Most normal and tumor cells are protected from tumor necrosis factor α (TNFα)-induced apoptosis. Here, we identify the MAP3 kinase tumor progression locus-2 (TPL2) as a player contributing to the protection of a subset of tumor cell lines. The combination of TPL2 knockdown and TNFα gives rise to a synthetic lethality phenotype via receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-dependent and -independent mechanisms. Whereas wild-type TPL2 rescues the phenotype, its kinase-dead mutant does not. Comparison of the molecular events initiated by small interfering RNA for TPL2 (siTPL2) ± TNFα in treatment-sensitive and -resistant lines revealed that the activation of caspase-8, downstream of miR-21-5p and cFLIP, is the dominant TPL2-dependent event. More important, comparison of the gene expression profiles of all of the tested cell lines results in the clustering of sensitive and resistant lines into distinct groups, providing proof of principle for the feasibility of generating a predictive tool for treatment sensitivity.