Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an endogenous secreted peptide and, in preclinical studies, preferentially induces apoptosis in tumor cells rather than in normal cells. The acquisition of resistance in cells exposed to TRAIL or its mimics limits their clinical efficacy. Because kinases are intimately involved in the regulation of apoptosis, we systematically characterized kinases involved in TRAIL signaling. Using RNA interference (RNAi) loss-of-function and cDNA overexpression screens, we identified 169 protein kinases that influenced the dynamics of TRAIL-induced apoptosis in the colon adenocarcinoma cell line DLD-1. We classified the kinases as sensitizers or resistors or modulators, depending on the effect that knockdown and overexpression had on TRAIL-induced apoptosis. Two of these kinases that were classified as resistors were PX domain-containing serine/threonine kinase (PXK) and AP2-associated kinase 1 (AAK1), which promote receptor endocytosis and may enable cells to resist TRAIL-induced apoptosis by enhancing endocytosis of the TRAIL receptors. We assembled protein interaction maps using mass spectrometry-based protein interaction analysis and quantitative phosphoproteomics. With these protein interaction maps, we modeled information flow through the networks and identified apoptosis-modifying kinases that are highly connected to regulated substrates downstream of TRAIL. The results of this analysis provide a resource of potential targets for the development of TRAIL combination therapies to selectively kill cancer cells.
Original languageEnglish
Article numberrs3
JournalScience Signaling
Volume8
Issue number371
ISSN1945-0877
DOIs
Publication statusPublished - 2015
CitationsWeb of Science® Times Cited: No match on DOI

    Research areas

  • apoptosis, cancer Neoplasms (MeSH) neoplastic disease, Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] DLD-1 cell line cell_line human colon adenocarcinoma cells, AAK1, cDNA complementary DNA expression, protein kinase 372092-80-3 EC 2.7.13.3, PXK, TRAIL receptor, TRAIL signaling, 02508, Cytology - Human, 10060, Biochemistry studies - General, 10062, Biochemistry studies - Nucleic acids, purines and pyrimidines, 10802, Enzymes - General and comparative studies: coenzymes, 12512, Pathology - Therapy, 22002, Pharmacology - General, 22005, Pharmacology - Clinical pharmacology, 24004, Neoplasms - Pathology, clinical aspects and systemic effects, combination therapy therapeutic and prophylactic techniques, clinical techniques, mass spectrometry-based protein interaction analysis laboratory techniques, spectrum analysis techniques, RNA interference RNAi laboratory techniques, genetic techniques, Biochemistry and Molecular Biophysics, Pharmacology, Tumor Biology, BIOCHEMISTRY, CELL, NF-KAPPA-B, DEPENDENT PROTEIN-KINASE, INTEGRIN-LINKED KINASE, CASPASE RECRUITMENT DOMAIN, HIGHLY OPTIMIZED TOLERANCE, LIGAND-INDUCED APOPTOSIS, LIGHT-INDUCED APOPTOSIS, ALPHA-INDUCED APOPTOSIS, CELL-CYCLE ARREST, CANCER-CELLS, Research Resources, Systems Biology

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