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      Lipid metabolic vulnerabilities of multiple myeloma

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          Abstract

          Multiple myeloma (MM) is the second most common hematological malignancy worldwide, characterized by abnormal proliferation of malignant plasma cells within a tumor-permissive bone marrow microenvironment. Metabolic dysfunctions are emerging as key determinants in the pathobiology of MM. In this review, we highlight the metabolic features of MM, showing how alterations in various lipid pathways, mainly involving fatty acids, cholesterol and sphingolipids, affect the growth, survival and drug responsiveness of MM cells, as well as their cross-talk with other cellular components of the tumor microenvironment. These findings will provide a new path to understanding the mechanisms underlying how lipid vulnerabilities may arise and affect the phenotype of malignant plasma cells, highlighting novel druggable pathways with a significant impact on the management of MM.

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          Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease

          Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.
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            Mechanisms and regulation of cholesterol homeostasis

            Cholesterol homeostasis is vital for proper cellular and systemic functions. Disturbed cholesterol balance underlies not only cardiovascular disease but also an increasing number of other diseases such as neurodegenerative diseases and cancers. The cellular cholesterol level reflects the dynamic balance between biosynthesis, uptake, export and esterification - a process in which cholesterol is converted to neutral cholesteryl esters either for storage in lipid droplets or for secretion as constituents of lipoproteins. In this Review, we discuss the latest advances regarding how each of the four parts of cholesterol metabolism is executed and regulated. The key factors governing these pathways and the major mechanisms by which they respond to varying sterol levels are described. Finally, we discuss how these pathways function in a concerted manner to maintain cholesterol homeostasis.
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              Sphingolipid metabolism in cancer signalling and therapy

              Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure-function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P-S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.
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                Author and article information

                Contributors
                amodio@unicz.it
                Journal
                Clin Exp Med
                Clin Exp Med
                Clinical and Experimental Medicine
                Springer International Publishing (Cham )
                1591-8890
                1591-9528
                28 August 2023
                28 August 2023
                2023
                : 23
                : 7
                : 3373-3390
                Affiliations
                [1 ]Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, ( https://ror.org/0530bdk91) Viale Europa, Campus Germaneto, 88100 Catanzaro, Italy
                [2 ]Department of Biology, Ecology and Heart Sciences, University of Calabria, ( https://ror.org/02rc97e94) Arcavacata Di Rende, Cosenza, Italy
                [3 ]Centro Universitário São Camilo, ( https://ror.org/04a6gpn58) São Paulo, Brazil
                Article
                1174
                10.1007/s10238-023-01174-2
                10618328
                37639069
                ce774638-ba8c-474d-948b-d8224f03413b
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 July 2023
                : 15 August 2023
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro,Italy
                Award ID: 24449
                Award ID: 24449
                Award ID: 24449
                Award ID: 24449
                Award ID: 24449
                Award Recipient :
                Funded by: Università degli studi "Magna Graecia" di Catanzaro
                Categories
                Review
                Custom metadata
                © Springer Nature Switzerland AG 2023

                Medicine
                cholesterol,fatty acids,lipid metabolism,metabolic reprogramming,multiple myeloma,sphingolipids

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