Research Papers:

Inorganic polyphosphate as an energy source in tumorigenesis

Jerusha Boyineni, Simone T. Sredni, Naira V. Margaryan, Lusine Demirkhanyan, Michael Tye, Robert Johnson, Fernando Gonzalez-Nilo, Mary J.C. Hendrix, Evgeny Pavlov, Marcelo B. Soares, Eleonora Zakharian _ and Sergey Malchenko _

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Oncotarget. 2020; 11:4613-4624. https://doi.org/10.18632/oncotarget.27838

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Jerusha Boyineni1, Simone T. Sredni2,3, Naira V. Margaryan4, Lusine Demirkhanyan1, Michael Tye1, Robert Johnson1, Fernando Gonzalez-Nilo5,6, Mary J.C. Hendrix7, Evgeny Pavlov8, Marcelo B. Soares1, Eleonora Zakharian1,* and Sergey Malchenko1,*

1 Department of Cancer Biology & Pharmacology, University of Illinois College of Medicine, Peoria, Illinois, USA

2 Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA

3 Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA

4 Department of Biochemistry, Robert C. Byrd Health Sciences Center and Cancer Institute, West Virginia University, Morgantown, West Virginia, USA

5 Center for Bioinformatics and Integrative Biology, Universidad Andres Bello, Santiago, Chile

6 Centro Interdisciplinario de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile

7 Department of Biology, Shepherd University, Shepherdstown, West Virginia, USA

8 Department of Molecular Pathobiology, New York University, College of Dentistry, New York, New York, USA

* These authors contributed equally to this work

Correspondence to:

Eleonora Zakharian,email: [email protected]
Sergey Malchenko,email: [email protected]

Keywords: polyphosphate; energy source; OXPHOS; glycolysis; metabolism

Received: August 22, 2020     Accepted: November 20, 2020     Published: December 15, 2020

Copyright: © 2020 Boyineni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.

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