Metabolic studies investigating the mechanics of cancer cell proliferation have been critical to understanding resource allocation driving tumorigenesis. Generally, proliferating cells eschew efficient energy production in favour of metabolic pathways that generate the essential macromolecular building blocks necessary to grow in size and number, classically termed the Warburg effect. In a new study from the Koch Institute for Integrative Cancer Research at MIT, researchers employ an ingenious combination of isotopic labeling and mass spectrometry, and use in vitro models of proliferating mammalian cells, including non-small cell lung cancer cell lines, to provide new insights into the what fuels cancer cell growth (1).
Non-glutamine amino acids are diverted almost exclusively to cellular mass build-up during cancer cell proliferation.
Glucose and the amino acid glutamine continue to be the top two contributors to the carbon pool in growing cancer cells, accounting of 10% cell mass each, which provides a quantitative proof to the Warburg effect. Interestingly, the research revealed that the exogenous amino acids (other than glutamine) contributed to almost 40% of cellular mass. Paradoxically, the most consumed metabolite glucose is utilized with the least efficiency as most of it is fated to be excreted as lactate by the cancer cells. In contrast, non-glutamine amino acids that are consumed at much lower rates by cancer cells, are diverted almost exclusively to cellular mass build-up during proliferation (2). This observation gives credence to the observations that when the supply of amino acids is limited, cancer cells quickly resort to protein scavenging to fuel their growth (3).
Glucose supply appears to be able to compensate for the absence of other macromolecules.
However, favoring uptake of macromolecules for cellular build-up instead of biosynthesis is also not true in every case. For example, in case of amino acid asparagine, aspartate, glutamate, and proline, glutamine-derived carbon and nitrogen contributes for much of these cellular mass of these amino acids irrespective of their exogenous supply levels, indicating that despite the higher energy costs, there could be a benefit to adopting this modality as a resistance mechanism for reducing reliance on exogenous supply of metabolites for growth. Additionally, glucose supply appears to be able to compensate for the absence of other macromolecules such as serine or fatty acids, with glucose-derived carbon along with glutamine-derived nitrogen supplying much of the biomass for nucleic acid synthesis that is crucial for cellular proliferation.
Overall, the new study from the Koch Institute (1), provides a quantitative confirmation of the Warburg effect, but also highlights the importance of rapid glycolysis and glutaminolysis for proliferating cells to generate metabolic products beyond biomass carbon.
Mukundh Balasubramanian, PhD, BioSistemika LLC