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Contributed by Carlo M. Croce, May 21, 2019 (sent for review January 29, 2019; reviewed by Emad S. Alnemri and Wafik El-Deiry)
Significance
Tumor necrosis factor α (TNFα) fails to induce apoptosis in most tumor cells. Defining the mechanism(s) responsible for the protection of these cells from TNFα-induced apoptosis may have significant therapeutic implications. Here, we show that tumor progression locus-2 (TPL2), a MAP3 kinase activated by TNFα, protects from TNFα-induced apoptosis by preventing the activation of caspase-8, and that the combination of TPL2 knockdown and TNFα treatment induces synthetic lethality. More important, sensitivity to synthetic lethality can be predicted from the gene expression profiles of the tumor cells. In addition to their therapeutic potential, these results identify an important node in TNFα signaling.
Abstract
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.
Footnotes
↵1Present address: Clinical Biomarkers Department, Agios Pharmaceuticals, Cambridge, MA 02139.
↵2Present address: Department of Medicine, Tufts Medical Center, Boston, MA 02111.
↵3Present address: Division of Gastroenterology, Department of Medicine, Duke University, Durham, NC 27710.
- ↵4To whom correspondence may be addressed. Email: carlo.croce{at}osumc.edu or philip.tsichlis{at}osumc.edu.
Author contributions: O.B.S. and P.N.T. designed research; O.B.S., M.D.P., E.A.-F., V.T., W.R., and G.T. performed research; J.R., K.D., and C.M.C. contributed new reagents/analytic tools; O.B.S., M.D.P., and E.A.-F. analyzed data; O.B.S. and P.N.T. wrote the paper; and M.D.P. contributed the bioinformatics analyses.
Reviewers: E.S.A., Thomas Jefferson University; and W.E.-D., Brown University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1901465116/-/DCSupplemental.
Published under the PNAS license.
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The combination of TPL2 knockdown and TNFα causes synthetic lethality via caspase-8 activation in human carcinoma cell lines
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