Abstract
SummaryUnlike most cell types, many cancer cells survive at low extracellular pH (pHe), a chemical signature of tumors. Genes that facilitate survival under acid stress are therefore potential targets for cancer therapies. We performed a genome-wide CRISPR-Cas9 cell viability screen at physiological and acidic conditions to systematically identify gene knockouts associated with pH-related fitness defects in colorectal cancer cells. Knockouts of genes involved in oxidative phosphorylation (NDUFS1) and iron-sulfur cluster biogenesis (IBA57, NFU1) grew well at physiological pHe, but underwent profound cell death under acidic conditions. We identified several small-molecule inhibitors of mitochondrial metabolism that can kill cancer cells at low pHe only. Xenografts established from NDUFS1−/− cells grew considerably slower than their wild-type controls, but growth could be stimulated with systemic bicarbonate therapy that lessens the tumoral acid stress. These findings raise the possibility of therapeutically targeting mitochondrial metabolism in combination with acid stress as a cancer treatment option.
Highlights
Cancer cell proliferation, without its normal checks and controls, leads to a high metabolic rate
These observations suggest that tumor acidosis and hypoxia are maintained by distinct molecular pathways, and that cancer cells can be exposed to various combinations of acid and hypoxic stress
Genome-wide CRISPR-Cas9 screen identifies genes essential for survival under low and physiological pHe To identify specific genes that are essential for survival under acidic conditions, we performed a genome-wide CRISPRCas9 screen and validated the highest-ranking hits on a case-by-case basis
Summary
Without its normal checks and controls, leads to a high metabolic rate. Mitochondrial oxidative phosphorylation (OXPHOS) can occur even under restricted access to O2 in moderately hypoxic tissues (Fukuda et al, 2007); if, the energy harnessed by mitochondrial metabolism becomes inadequate, a fallback option is to enhance the glycolytic rate (Denko, 2008) This re-routing is self-limiting, as the accumulation of acidic products feeds back negatively on glycolysis (Corbet et al, 2014, Lamonte et al, 2013). Rohani and colleagues (Rohani et al, 2019) have shown that acidosis can occur in normoxic regions, such as the tumor-stroma interface, whereas hypoxic conditions are more likely to be found at the tumor core These observations suggest that tumor acidosis and hypoxia are maintained by distinct molecular pathways, and that cancer cells can be exposed to various combinations of acid and hypoxic stress
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