Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage at the nuclear periphery.

Autor:	Ramos AD; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Liang YY; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore., Surova O; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Bacanu S; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Gerault MA; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Mandal T; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Ceder S; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Langebäck A; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Österroos A; Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden., Ward GA; Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, UK., Bergh J; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Wiman KG; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden., Lehmann S; Department of Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden; Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden., Prabhu N; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore., Lööf S; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: sara.loof@ki.se., Nordlund P; Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore. Electronic address: par.nordlund@ki.se.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Oct 22; Vol. 43 (10), pp. 114784. Date of Electronic Publication: 2024 Oct 03.
DOI:	10.1016/j.celrep.2024.114784
Abstrakt:	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. Competing Interests: Declaration of interests P.N. is the inventor of patents related to the CETSA method and is a cofounder and board member of Pelago Biosciences AB. P.N., A.D.R., S. Lööf, S.B., and M.-A.G. are inventors on patent applications related to CETSA-based biomarkers. K.G.W. is a cofounder and shareholder of Aprea Therapeutics, a company that develops p53-targeted cancer therapy, including APR-246. K.G.W. has previously received financial support and a salary from Aprea Therapeutics. G.A.W. is a full-time employee of Astex Pharmaceuticals. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu