TY - JOUR
T1 - Mitochondrial rewiring drives metabolic adaptation to NAD(H) shortage in triple negative breast cancer cells
AU - Carreira, Agata Sofia Assuncao
AU - Ravera, Silvia
AU - Zucal, Chiara
AU - Thongon, Natthakan
AU - Irene, Caffa
AU - Astigiano, Cecilia
AU - Bertola, Nadia
AU - Buongiorno, Arianna
AU - Roccuzzo, Michela
AU - Bisio, Alessandra
AU - Pardini, Barbara
AU - Nencioni, Alessio
AU - Bruzzone, Santina
AU - Provenzani, Alessandro
N1 - Publisher Copyright:
© 2023
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
KW - Drug resistance
KW - FK866
KW - Metabolic adaptation
KW - Mitochondrial fitness
KW - MPC2
KW - NAMPT
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U2 - 10.1016/j.neo.2023.100903
DO - 10.1016/j.neo.2023.100903
M3 - Article
C2 - 37148658
AN - SCOPUS:85154552165
SN - 1522-8002
VL - 41
JO - Neoplasia (United States)
JF - Neoplasia (United States)
M1 - 100903
ER -