Journal article
Integrative analysis of kinase networks in TRAIL-induced apoptosis provides a source of potential targets for combination therapy
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.
| Language: | English |
|---|---|
| Publisher: | American Association for the Advancement of Science |
| Year: | 2015 |
| Pages: | rs3 |
| ISSN: | 19379145 and 19450877 |
| Types: | Journal article |
| DOI: | 10.1126/scisignal.2005700 |
| ORCIDs: | Schoof, Erwin M. and 0000-0003-0420-4839 |
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 AAK1 ALPHA-INDUCED APOPTOSIS BIOCHEMISTRY Biochemistry and Molecular Biophysics CANCER-CELLS CASPASE RECRUITMENT DOMAIN CELL CELL-CYCLE ARREST DEPENDENT PROTEIN-KINASE HIGHLY OPTIMIZED TOLERANCE INTEGRIN-LINKED KINASE LIGAND-INDUCED APOPTOSIS LIGHT-INDUCED APOPTOSIS NF-KAPPA-B PXK Pharmacology Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] DLD-1 cell line cell_line human colon adenocarcinoma cells RNA interference RNAi laboratory techniques, genetic techniques Research Resources SDG 3 - Good Health and Well-being Systems Biology TRAIL receptor TRAIL signaling Tumor Biology apoptosis cDNA complementary DNA expression cancer Neoplasms (MeSH) neoplastic disease combination therapy therapeutic and prophylactic techniques, clinical techniques mass spectrometry-based protein interaction analysis laboratory techniques, spectrum analysis techniques protein kinase 372092-80-3 EC 2.7.13.3
AAK1 protein, human Adenocarcinoma Apoptosis Cell Line, Tumor Colonic Neoplasms HEK293 Cells Humans Intracellular Signaling Peptides and Proteins Neoplasm Proteins Nerve Tissue Proteins PXK protein, human Protein Serine-Threonine Kinases Signal Transduction TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human
