ICG-001 affects DRP1 activity and ER stress correlative with its anti-proliferative effect
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Heidi Zinecker1, Djamila Ouaret2, Daniel Ebner3, Moritz M. Gaidt4, Steve Taylor5, Anna Aulicino1, Marta Jagielowicz1, Veit Hornung4 and Alison Simmons1
1MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
2Department of Oncology, Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
3Target Discovery Institute, University of Oxford, Oxford, OX3 7FZ, United Kingdom
4Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, 81377, Germany
5Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
Alison Simmons, email: [email protected]
Keywords: DRP1; drug screening; ICG-001; ER stress; colorectal cancer
Received: February 08, 2017 Accepted: October 17, 2017 Published: November 01, 2017
Mitochondria form a highly dynamic network driven by opposing scission and fusion events. DRP1 is an essential modulator of mitochondrial fission and dynamics within mammalian cells. Its fission activity is regulated by posttranslational modifications such as activating phosphorylation at serine 616. DRP1 activity has recently been implicated as being dysregulated in numerous human disorders such as cancer and neurodegenerative diseases. Here we describe the development of a cell-based screening assay to detect DRP1 activation. We utilized this to undertake focused compound library screening and identified potent modulators that affected DRP1 activity including ICG-001, which is described as WNT/β-catenin signaling inhibitor. Our findings elucidate novel details about ICG-001’s mechanism of action (MOA) in mediating anti-proliferative activity. We show ICG-001 both inhibits mitochondrial fission and activates an early endoplasmic reticulum (ER) stress response to induce cell death in susceptible colorectal cancer cell lines.
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