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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Serebrennikova, OB; Paraskevopoulou, MD; Aguado-Fraile, E; Taraslia, V; Ren, W; Thapa, G; Roper, J; Du, K; Croce, CM; Tsichlis, PN

Published Date

  • July 9, 2019

Published In

Volume / Issue

  • 116 / 28

Start / End Page

  • 14039 - 14048

PubMed ID

  • 31239343

Pubmed Central ID

  • 31239343

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1901465116

Language

  • eng

Conference Location

  • United States