Cysteine Is Required for Preventing Ferroptosis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) cells circumvent the consequences of increased reactive oxygen species (ROS) production—which can be caused by mutational activation of KRAS, as one example—by upregulating metabolic processes that yield cysteine-derived metabolites, such as glutathione, that reduce ROS levels. Hypothesizing that cysteine import would thus be key to the survival of PDAC cells, Badgley and colleagues performed in vitro experiments using human PDAC cell lines, which confirmed that PDAC cells depend on cysteine import. Specifically, PDAC cells deprived of cysteine by various means (including inhibition of the cysteine importer system x_c⁻) underwent ferroptosis, an iron-dependent form of programmed cell death characterized by a lethal buildup of lipid peroxides. In a mouse model of PDAC, deletion of the gene encoding a subunit of system x_c⁻ (Slc7a11) in established tumors substantially increased median survival and even caused complete tumor regression in one mouse. Tumors in which Slc7a11 was deleted exhibited microscopic characteristics abnormal for PDAC tumors, including large lipid droplets and structurally defective mitochondria, and had increased expression of ferroptosis-related genes. Interestingly, although previous work found that cysteine's role in ferroptosis is related to the synthesis of glutathione, inhibition of glutathione biosynthesis alone in human PDAC cell lines did not increase lipid ROS levels or cause ferroptosis. Instead, a reduction in levels of coenzyme A, also synthesized from cysteine, cooperated with glutathione loss to induce ferroptosis. Notably, in a mouse model of PDAC, treatment with cyst(e)inase, which degrades cysteine, caused tumor stabilization or regression in all mice. Tumors from these mice exhibited the characteristic signs of ferroptosis observed with Slc7a11 deletion, including abnormally large lipid droplets and mitochondrial aberrations. Collectively, these results provide further evidence that PDAC is dependent on cysteine metabolism to prevent ROS-induced ferroptosis and suggest that cysteine depletion may be a useful clinical strategy.

Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V, et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020;368:85–9.

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