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  3. Mitochondrial rewiring drives metabolic adaptation to NAD(H) shortage in triple negative breast cancer cells

Mitochondrial rewiring drives metabolic adaptation to NAD(H) shortage in triple negative breast cancer cells

  • Neoplasia. 2023 May 4;41:100903. doi: 10.1016/j.neo.2023.100903.
Agata Sofia Assuncao Carreira 1,  Silvia Ravera 2,  Chiara Zucal 3,  Natthakan Thongon 4,  Caffa Irene 5,  Cecilia Astigiano 6,  Nadia Bertola 7,  Arianna Buongiorno 8,  Michela Roccuzzo 9,  Alessandra Bisio 10,  Barbara Pardini 11,  Alessio Nencioni 12,  Santina Bruzzone 13,  Alessandro Provenzani 14
Affiliations

Affiliations

  • 1 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: agata.carreira@unitn.it.
  • 2 Department of Experimental Medicine, University of Genoa, Genoa, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy. Electronic address: silvia.ravera@unige.it.
  • 3 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: chiara.zucal@unitn.it.
  • 4 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy. Electronic address: th.natthakan@gmail.com.
  • 5 Department of Internal Medicine, University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy. Electronic address: Irene.Caffa@unige.it.
  • 6 Department of Experimental Medicine, University of Genoa, Genoa, Italy. Electronic address: cecilia.astigiano@gmail.com.
  • 7 Department of Experimental Medicine, University of Genoa, Genoa, Italy. Electronic address: nadia.bertola@gmail.com.
  • 8 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: aribuongi00@gmail.com.
  • 9 Advanced Imaging Core Facility, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: michela.rocuzzo@unitn.it.
  • 10 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: alessandra.bisio@unitn.it.
  • 11 Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy; Italian Institute for Genomic Medicine (IIGM), Candiolo, Italy. Electronic address: barbara.pardini@iigm.it.
  • 12 Department of Internal Medicine, University of Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy. Electronic address: alessio.nencioni@unige.it.
  • 13 Department of Experimental Medicine, University of Genoa, Genoa, Italy. Electronic address: santina.bruzzone@unige.it.
  • 14 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: alessandro.provenzani@unitn.it.
PMID: 37148658 DOI: 10.1016/j.neo.2023.100903
Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a key metabolic Enzyme in NAD+ synthesis pathways and is found upregulated in several tumors, depicting NAD(H) lowering agents, like the NAMPT Inhibitor FK866, as an appealing approach for Anticancer therapy. Like other small molecules, FK866 triggers chemoresistance, observed in several Cancer cellular models, which can prevent its clinical application. The molecular mechanisms sustaining the acquired of resistance to FK866 were studied in a model of triple negative breast Cancer (MDA-MB-231 parental - PAR), exposed to increasing concentrations of the small molecule (MDA-MB-231 resistant - RES). RES cells are not sensitive to verapamil or cyclosporin A, excluding a potential role of increased efflux pumps activity as a mechanism of resistance. Similarly, the silencing of the Enzyme Nicotinamide Riboside Kinase 1 (NMRK1) in RES cells does not increase FK866 toxicity, excluding this pathway as a compensatory mechanism of NAD+ production. Instead, Seahorse metabolic analysis revealed an increased mitochondrial spare respiratory capacity in RES cells. These cells presented a higher mitochondrial mass compared to the FK866-sensitive counterparts, as well as an increased consumption of pyruvate and succinate for energy production. Interestingly, co-treatment of PAR cells with FK866 and the mitochondrial pyruvate carrier (MPC) inhibitors UK5099 or rosiglitazone, as well as with the transient silencing of MPC2 but not of MPC1, induces a FK866-resistant phenotype. Taken together, these results unravel novel mechanisms of cell plasticity to counteract FK866 toxicity, that, besides the previously described LDHA dependency, rely on mitochondrial rewiring at functional and energetic levels.

Keywords

Drug resistance; FK866; MPC2; Metabolic adaptation; Mitochondrial fitness; NAMPT.

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