Lack of Cystine Kills Renal Cancer Cells in Mouse Model

Restricting access to a specific extracellular nutrient—the amino acid cysteine—caused the death of certain types of renal cancer cells both in culture and in a kidney cancer mouse model.

Being transformed may reprogram a cancer cell's metabolism and addict it to certain very specific extracellular nutrients. Deprivation of these nutrients may therefore represent a therapeutic opportunity, but predicting which nutrients cancer cells become addicted to remains difficult.

Investigators at Duke University (Durham, NC, USA) worked with clear-cell renal cancer cells (ccRCC) that did or did not carry the von Hippel–Lindau tumor suppressor (VHL) gene. They performed a nutrigenetic screen with these cells by deleting each of the 15 amino acids from their growth media, one by one.

They reported in the February 1, 2016, online edition of the journal Cancer Research that cystine deprivation triggered rapid programmed necrosis in VHL-deficient cell lines and primary ccRCC tumor cells, but not in VHL-restored counterparts. Each molecule of cystine is made from two molecules of cysteine, another sulfur-containing amino acid.

VHL normally suppresses the activity of tumor necrosis factor alpha (TNF-alpha). High levels of TNF-alpha activity generate free radicals that are normally degraded by cystine. In VHL mutant cells TNF-alpha was overexpressed and lack of cystine enabled the free radicals to trigger necrosis of the cancer cells. When mice with implanted renal cell carcinoma tumors were treated with sulfasalazine, a drug that blocked cystine uptake, the tumors displayed significantly delayed growth and necrosis.

"We found that the same machinery that makes these tumors so aggressive also makes them vulnerable to nutrient deprivation," said senior author Dr. Jen-Tsan Chi, associate professor of molecular biology and microbiology at Duke University. "It is like we are beating it at its own game. Most chemotherapies kill cancer cells through apoptosis, and the cancer cells that escape apoptosis are the root cause of chemotherapy resistance and tumor progression. Cystine starvation treatments could address resistance by killing cells through a different mechanism."

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