Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage at the nuclear periphery
Anderson Daniel Ramos,
Ying Yu Liang,
Olga Surova,
Smaranda Bacanu,
Marc-Antoine Gerault,
Tamoghna Mandal,
Sophia Ceder,
Anette Langebäck,
Albin Österroos,
George A. Ward,
Jonas Bergh,
Klas G. Wiman,
Sören Lehmann,
Nayana Prabhu,
Sara Lööf,
Pär Nordlund
Affiliations
Anderson Daniel Ramos
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Ying Yu Liang
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore
Olga Surova
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Smaranda Bacanu
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Marc-Antoine Gerault
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Tamoghna Mandal
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Sophia Ceder
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Anette Langebäck
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Albin Österroos
Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden
George A. Ward
Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, UK
Jonas Bergh
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Klas G. Wiman
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
Sören Lehmann
Department of Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden; Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden
Nayana Prabhu
Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore
Sara Lööf
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Corresponding author
Pär Nordlund
Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Molecular and Cell Biology, A∗STAR, Singapore 138673, Singapore; Corresponding author
Summary: Cellular phenotypes of apoptosis, as well as the activation of apoptosis caspase cascades, are well described. However, sequences and locations of early biochemical effector events after apoptosis initiation are still only partly understood. Here, we use integrated modulation of protein interaction states-cellular thermal shift assay (IMPRINTS-CETSA) to dissect the cellular biochemistry of early stages of apoptosis at the systems level. Using 5 families of cancer drugs and a new CETSA-based method to monitor the cleavage of caspase targets, we discover the initial biochemistry of the effector stage of apoptosis for all the studied drugs being focused on the peripheral nuclear region rather than the cytosol. Despite very different candidate apoptosis-inducing mechanisms of the drug families, as revealed by the CETSA data, they converge into related biochemical modulations in the peripheral nuclear region. This implies a higher control of the localization of the caspase cascades than previously anticipated and highlights the nuclear periphery as a critical vulnerability for cancer therapies.
