Abstract
Self-sustained cell proliferation constitutes one hallmark of cancer enabled by aerobic glycolysis which is characterized by imbalanced glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) activity, named the Warburg effect. The C1q binding protein (C1QBP; gC1qR) is pivotal for mitochondrial protein translation and thus OXPHOS activity. Due to its fundamental role in balancing OXPHOS and glycolysis, c1qbp−/− mice display embryonic lethality, while gC1qR is excessively up-regulated in cancer. Although gC1qR encompasses an N-terminal mitochondrial leader it is also located in other cellular compartments. Hence, we aimed to investigate mechanisms regulating gC1qR cellular localization and its impact on tumor cell metabolism. We identified two caspase-1 cleavage sites in human gC1qR. GC1qR cleavage by active caspase-1 was unraveled as a cellular mechanism that prevents mitochondrial gC1qR import, thereby enabling aerobic glycolysis and enhanced cell proliferation. Ex vivo, tumor grading correlated with non-mitochondrial-located gC1qR as well as with caspase-1 activation in colorectal carcinoma patients. Together, active caspase-1 cleaves gC1qR and boosts aerobic glycolysis in tumor cells.
Highlights
Proliferation and differentiation of cells comprise cellular processes that require high energy levels
Most tumor cells fine-tune their metabolism from balanced oxidative phosphorylation (OXPHOS) to fast but inefficient aerobic glycolysis, called the Warburg effect (3, 4)
The question remains, whether regulation of the level of gC1qR localized in the mitochondria leads to a secondary regulation of energy provided by mitochondrial oxidative phosphorylation, thereby allowing the switch to aerobic glycolysis
Summary
Proliferation and differentiation of cells comprise cellular processes that require high energy levels. While it is most likely to be a general mechanism that proliferating cells generate their energy via aerobic glycolysis, differentiated post-mitotic cells are known to maintain their energy level via the mitochondrial oxidative phosphorylation (OXPHOS) system (1). The metabolic switch from cytosolic aerobic glycolysis to the mitochondrial OXPHOS system is suggested to influence the transition of transient amplifying cells into post-mitotic cells (2). Mechanisms that enable the cells to switch between these metabolic pathways still remain elusive. It is thought that the metabolic switch from gaining energy primarily via balanced mitochondrial OXPHOS toward aerobic glycolysis, the so-called Warburg effect, is an important. Caspase-1 Cleaves OXPHOS-Driving gC1qR driver of tumor formation and proliferation (1, 3–5). It was hypothesized that tumor cells are characterized mostly by mitochondria dysfunction, while it is understood that tumor cells still display functional mitochondria (6)
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