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

doi:10.1016/j.celrep.2024.114784

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

Cell Rep. 2024 Oct 3;43(10):114784. doi: 10.1016/j.celrep.2024.114784. Online ahead of print.

Authors

Anderson Daniel Ramos¹, Ying Yu Liang², Olga Surova¹, Smaranda Bacanu¹, Marc-Antoine Gerault¹, Tamoghna Mandal¹, Sophia Ceder¹, Anette Langebäck¹, Albin Österroos³, George A Ward⁴, Jonas Bergh¹, Klas G Wiman¹, Sören Lehmann⁵, Nayana Prabhu⁶, Sara Lööf⁷, Pär Nordlund⁸

Affiliations

¹ Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden.
² Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
³ Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden.
⁴ Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, UK.
⁵ Department of Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden; Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden.
⁶ Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
⁷ Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: sara.loof@ki.se.
⁸ 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.

PMID: 39365699
DOI: 10.1016/j.celrep.2024.114784

Abstract

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.

Keywords: CETSA; CP: Cancer; CP: Cell biology; IAP inhibitors; PI3K inhibitors; apoptosis; cancer drugs; caspase cleavage; glutathione metabolism; mass spectrometry; proteomics; taxanes.