Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis.

Autor: Skorda A; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark., Lauridsen AR; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark., Wu C; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark., Huang J; Department of Biomedicine, Aarhus University, Aarhus, Denmark., Mrackova M; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark., Winther NI; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark., Jank V; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark., Sztupinszki Z; Translational Cancer Genomics, Danish Cancer Institute, Copenhagen, Denmark., Strauss R; Genome Integrity Group, Danish Cancer Institute, Copenhagen, Denmark., Bilgin M; Lipidomics Core Facility, Danish Cancer Institute, Copenhagen, Denmark., Maeda K; Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen, Denmark., Liu B; Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen, Denmark., Luo Y; Department of Biomedicine, Aarhus University, Aarhus, Denmark.; Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark., Jäättelä M; Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen, Denmark.; Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Kallunki T; Cancer Invasion and Resistance, Danish Cancer Institute, Strandboulevarden 49, 2100, Copenhagen, Denmark. tk@cancer.dk.; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. tk@cancer.dk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2023 Aug; Vol. 42 (33), pp. 2495-2506. Date of Electronic Publication: 2023 Jul 07.
DOI: 10.1038/s41388-023-02771-x
Abstrakt: Cancer cells are dependent on cholesterol, and they possess strictly controlled cholesterol homeostasis mechanisms. These allow them to smoothly switch between cholesterol synthesis and uptake to fulfill their needs and to adapt environmental changes. Here we describe a mechanism of how cancer cells employ oncogenic growth factor signaling to promote uptake and utilization of extracellular cholesterol via Myeloid Zinc Finger 1 (MZF1)-mediated Niemann Pick C1 (NPC1) expression and upregulated macropinocytosis. Expression of p95ErbB2, highly oncogenic, standard-treatment resistant form of ErbB2 mobilizes lysosomes and activates EGFR, invasion and macropinocytosis. This is connected to a metabolic shift from cholesterol synthesis to uptake due to macropinocytosis-enabled flow of extracellular cholesterol. NPC1 increase facilitates extracellular cholesterol uptake and is necessary for the invasion of ErbB2 expressing breast cancer spheroids and ovarian cancer organoids, indicating a regulatory role for NPC1 in the process. The ability to obtain cholesterol as a byproduct of increased macropinocytosis allows cancer cells to direct the resources needed for the energy-consuming cholesterol synthesis towards other activities such as invasion. These results demonstrate that macropinocytosis is not only an alternative energy source for cancer cells but also an efficient way to provide building material, such as cholesterol, for its macromolecules and membranes.
(© 2023. The Author(s).)
Databáze: MEDLINE
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