Inger Ødum Nielsen1, Line Groth-Pedersen1, Jano Dicroce-Giacobini1, Anna Sofie Holm Jonassen1, Monika Mortensen1, Mesut Bilgin1, Kjeld Schmiegelow2,3, Marja Jäättelä4,5, Kenji Maeda6. 1. Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100, Copenhagen, Denmark. 2. Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet University Hospital, 2100, Copenhagen, Denmark. 3. Institute of Clinical Medicine, University of Copenhagen, 2200, Copenhagen, Denmark. 4. Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100, Copenhagen, Denmark. mj@cancer.dk. 5. Department of Cellular and Molecular Medicine, University of Copenhagen, 2200, Copenhagen, Denmark. mj@cancer.dk. 6. Cell Death and Metabolism Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center (DCRC), 2100, Copenhagen, Denmark. kenjim@cancer.dk.
Abstract
INTRODUCTION: Repurposing of cationic amphiphilic drugs (CADs) emerges as an attractive therapeutic solution against various cancers, including leukemia. CADs target lysosomal lipid metabolism and preferentially kill cancer cells via induction of lysosomal membrane permeabilization, but the exact effects of CADs on the lysosomal lipid metabolism remain poorly illuminated. OBJECTIVES: We aimed to systematically monitor CAD-induced alterations in the quantitative lipid profiles of leukemia cell lines in order to chart effects of CADs on the metabolism of various lipid classes present in these cells. METHODS: We conducted this study on eight cultured cell lines representing two leukemia types, acute lymphoblastic leukemia and acute myeloid leukemia. Mass spectrometry-based quantitative shotgun lipidomics was employed to quantify the levels of around 400 lipid species of 26 lipid classes in the leukemia cell lines treated or untreated with a CAD, siramesine. RESULTS: The two leukemia types displayed high, but variable sensitivities to CADs and distinct profiles of cellular lipids. Treatment with siramesine rapidly altered the levels of diverse lipid classes in both leukemia types. These included sphingolipid classes previously reported to play key roles in CAD-induced cell death, but also lipids of other categories. We demonstrated that the treatment with siramesine additionally elevated the levels of numerous cytolytic lysoglycerophospholipids in positive correlation with the sensitivity of individual leukemia cell lines to siramesine. CONCLUSIONS: Our study shows that CAD treatment alters balance in the metabolism of glycerophospholipids, and proposes elevation in the levels of lysoglycerophospholipids as part of the mechanism leading to CAD-induced cell death of leukemia cells.
INTRODUCTION: Repurposing of cationic amphiphilic drugs (CADs) emerges as an attractive therapeutic solution against various cancers, including leukemia. CADs target lysosomal lipid metabolism and preferentially kill cancer cells via induction of lysosomal membrane permeabilization, but the exact effects of CADs on the lysosomal lipid metabolism remain poorly illuminated. OBJECTIVES: We aimed to systematically monitor CAD-induced alterations in the quantitative lipid profiles of leukemia cell lines in order to chart effects of CADs on the metabolism of various lipid classes present in these cells. METHODS: We conducted this study on eight cultured cell lines representing two leukemia types, acute lymphoblastic leukemia and acute myeloid leukemia. Mass spectrometry-based quantitative shotgun lipidomics was employed to quantify the levels of around 400 lipid species of 26 lipid classes in the leukemia cell lines treated or untreated with a CAD, siramesine. RESULTS: The two leukemia types displayed high, but variable sensitivities to CADs and distinct profiles of cellular lipids. Treatment with siramesine rapidly altered the levels of diverse lipid classes in both leukemia types. These included sphingolipid classes previously reported to play key roles in CAD-induced cell death, but also lipids of other categories. We demonstrated that the treatment with siramesine additionally elevated the levels of numerous cytolytic lysoglycerophospholipids in positive correlation with the sensitivity of individual leukemia cell lines to siramesine. CONCLUSIONS: Our study shows that CAD treatment alters balance in the metabolism of glycerophospholipids, and proposes elevation in the levels of lysoglycerophospholipids as part of the mechanism leading to CAD-induced cell death of leukemia cells.
Entities:
Keywords:
Cancer; Lipidomics; Lysoglycerophospholipids; Lysosomes; Sphingolipids; Systems biology
Authors: Laia Cuesta-Casanovas; Jennifer Delgado-Martínez; Josep M Cornet-Masana; José M Carbó; Lise Clément-Demange; Ruth M Risueño Journal: Cancer Drug Resist Date: 2022-03-14