Abstract
Adaptation to anchorage-independent growth requires IDH1-mediated changes in citrate metabolism.
Major finding: Adaptation to anchorage-independent growth requires IDH1-mediated changes in citrate metabolism.
Mechanism: Extracellular matrix detachment in cancer cells triggers enhanced reductive carboxylation.
Impact: Adaptive metabolic changes are required to sustain anchorage-independent growth in cancer cells.
Cells grown as a monolayer take up glucose and glutamine via extracellular matrix–mediated signaling. As cancer cells acquire the capacity for anchorage-independent growth, these growth and survival signals must be replaced through mechanisms that remain unclear. To better understand the metabolic rewiring that occurs during anchorage-independent growth, Jiang and colleagues showed that H460 lung cancer cells grown as anchorage-independent spheroids displayed less pyruvate dehydrogenase activity compared to cells grown in a monolayer, as evidenced by reduced conversion of glucose-derived carbon into citrate, lower oxygen consumption, and increased inhibitory phosphorylation of pyruvate dehydrogenase kinase. During hypoxia, reductive carboxylation is enhanced in a HIF1-dependent manner, but anchorage-independent growth-associated changes in reductive metabolism occurred independently of hypoxia or HIF1. Further, anchorage independent growth–associated reductive metabolism changes required the cytosolic isocitrate dehydrogenase 1 (IDH1) enzyme, which catalyzes the interconversion of isocitrate and α-ketoglutarate, and the citrate transporter protein (CTP). Genetic or chemical suppression of IDH1 prevented reductive carboxylation in spheroids, and deletion of CTP inhibited the mitochondrial uptake of labeled citrate. Moreover, detachment of cells from a monolayer promoted the production of reactive oxygen species (ROS), particularly within the mitochondria, and was exacerbated upon deletion of IDH1 or CTP, or inhibition of the pentose phosphate pathway (PPP), a known regulator of ROS during matrix detachment. Keeping mitochondrial ROS levels low enough to sustain cell growth required IDH1-dependent reductive carboxylation in the cytosol, followed by transfer of citrate and/or isocitrate into the mitochondria via CTP, and oxidation of isocitrate by IDH2. This cycle transfers NADPH from the PPP into the mitochondria. Deletion of IDH1 or IDH2 specifically reduced the proliferation of detached cells in a manner that was dependent on mitochondrial ROS. Together, these results suggest that anchorage-independent growth promotes mitochondrial oxidative stress that must be counterbalanced by IDH1-driven changes in reductive carboxylation and citrate metabolism.
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