Abstract
Cancer cells have high demands for energy to maintain their exceedingly proliferative growth. However, the mechanism of energy expenditure in cancer is not well understood. We hypothesize that cancer cells might utilize energy-rich inorganic polyphosphate (polyP), as energetic reserve. PolyP is comprised of orthophosphates linked by phosphoanhydride bonds, as in ATP. Here, we show that polyP is highly abundant in several types of cancer cells, including brain tumor-initiating cells (BTICs), i.e., stem-like cells derived from a mouse brain tumor model that we have previously described. The polymer is avidly consumed during starvation of the BTICs. Depletion of ATP by inhibiting glycolysis and mitochondrial ATP-synthase (OXPHOS) further decreases the levels of polyP and alters morphology of the cells. Moreover, enzymatic hydrolysis of the polymer impairs the viability of cancer cells and significantly deprives ATP stores. These results suggest that polyP might be utilized as a source of phosphate energy in cancer. While the role of polyP as an energy source is established for bacteria, this finding is the first demonstration that polyP may play a similar role in the metabolism of cancer cells.
Highlights
The eukaryotic genome resulted from endosymbiosis between the progenitor of the eukaryotic lineage and an aerobic proteobacterium–the origin of mitochondria [1,2,3]
The switch from mitochondria oxidative metabolism to alternative energy sources is key in the cancer energy supply
Recognizing that evolutionarily mitochondria originated from aerobic proteobacterium [1,2,3], and that polyP is a ubiquitous polymer, we hypothesized that polyP may play a role in cancer cells as an energy source [22, 32], similar to its role in bacteria [34, 35] during starvation or hypoxia
Summary
The eukaryotic genome resulted from endosymbiosis between the progenitor of the eukaryotic lineage and an aerobic proteobacterium–the origin of mitochondria [1,2,3]. During nutritional stress or hypoxia, which are common factors in tumorigenesis, aerobic bacteria accumulate a ubiquitous polymer-inorganic polyphosphate (polyP), which contains high-energy phosphoanhydride bonds - and uses it as a steady source of energy [4]. The unique advantage of polyP as an energy source is that it can be directly converted into ATP without any intermediate steps and it does not require oxygen to generate energy [5]. PolyP is involved in regulation of different mitochondrial functions [25], including regulation of intracellular ATP [22]. It was shown recently that incubation of synthetic polyP with human osteogenic sarcoma cells led to accumulation of ADP and ATP in the extracellular space of the cells [26]. Many aspects of polyP function in mammalian organisms are not completely understood
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