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Cancer Metabolism and Metabolic Toxicity

The collective metabolic network of a cell is extensive and versatile, allowing the cell to allocate resources such as glucose and amino acids along different metabolic routes to serve specific biological processes. In cancer, several examples are known where cells modify their metabolism to preferentially ‘fuel’ cancer specific processes such as unchecked growth and cellular transformation, and thus targeting these pathways may provide therapeutic benefit.

On the other hand, within the cellular metabolic network, some metabolites appear to be inherently toxic or toxic when allowed to accumulate to abnormal levels, with a selective window of toxicity towards certain cell types or organs which is poorly understood. This is demonstrated in many amino acid breakdown disorders; in the example of phenylketonuria, severe toxicity in the developing brain occurs from loss of phenylalanine hydroxylase, an enzyme involved in phenylalanine catabolism, resulting in a toxic buildup of phenylalanine and phenylalanine byproducts.

We posit that within the metabolic network there are numerous metabolites with highly toxic properties, normally hidden as they are efficiently and quickly metabolized to a nontoxic form, comprising an 'endotoxome' that we continue to catalogue and explore (Lee et al, 2020). However, when these metabolites accumulate, such as due to impairment of the downstream detoxifying enzyme, they can wreak havoc in a cell. We have shown that toxic metabolites can thus be exploited to selectively kill cancer cells (Kim et al, 2015; Carlisle et al, 2020). We continue to explore how cancer cells differ in metabolic activities compared to normal cells, providing strategic points of attack to induce toxic metabolite accumulation.

It is increasingly appreciated that large scale metabolic changes accompany physiological and pathological changes in cell state, suggesting the possible involvement of toxic metabolic pathways in many processes outside of cancer. We are interested in collaborating with other groups to investigate the involvement of toxic metabolites in various pathological states such as neurodegenerative disorders and aging. We hope that our efforts in exploring toxic metabolite pathways will have far-reaching implications in better understanding cell metabolism and in treating various states of human disease.

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Investigating toxic metabolite pathways and metabolite detoxifying enzymes in cancer