Cystine Addiction: an Achilles’ Heel for Some Kidney Cancers?

February 5, 2016
Bryant Furlow

The majority of renal cell carcinomas harbor VHL tumor-suppressor gene deletions that cause tumor addiction to extracellular cystine-and cystine deprivation triggers tumor cell necrosis.

The majority of renal cell carcinomas (RCC) harbor VHL tumor-suppressor gene deletions that cause tumor addiction to extracellular cystine-and cystine deprivation triggers tumor cell necrosis, at least in mice, report researchers at Duke University School of Medicine in Durham, NC.

Results of this study were published February 1, 2016, in Cancer Research.  

“We found that the same machinery that makes these tumors so aggressive also makes them vulnerable to nutrient deprivation,” said senior study author Jen-Tsan Ashley Chi, PhD, an associate professor of molecular genetics and microbiology, in a Duke news release.

“It’s like we are beating it at its own game,” Dr. Chi remarked.

Cancer cells are nutrient-hungry and tumor metabolism is often altered in ways that leave cells “addicted” to specific nutrients. “Such nutrient addictions associated with oncogenic mutations may offer therapeutic opportunities; however, it remains difficult to predict these nutrient addictions,” noted the study coauthors.

Approximately 75% of RCC harbor deletion mutations for the VHL tumor-suppressor gene. In a series of nutrient-deprivation experiments, Dr. Chi and lead study author Xiaohu Tang, PhD, found that individually removing most amino acids from the growth media in which VHL-mutant RCC cells are cultured, does not kill tumor cells.

But when cystine was withheld, the cells died.

The team found that cystine deprivation “triggered rapid programmed necrosis in VHL-deficient RCC, but not in their VHL-restored counterparts.”

That’s likely because of VHL-absent cells’ production of elevated levels of tumor necrosis factor alpha (TNFα) and damaging free radicals from oxygen, the researchers believe. Cystine helps healthy cells maintain antioxidant levels to keep in check, they noted.

The elevated TNFα levels in VHL-deficient RCC “renders these cells susceptible to the necrosis signaling triggered by cystine deprivation,” the coauthors reported. Cystine-deprived necrosis in VHL-deficient kidney cancer cells “depends on reciprocal amplification of the Src-p38-Noxa signaling and TNFα-RIP1/3-MLKL necrosis pathways,” triggering programmed necrosis, they found.

“Together, our data reveal that the contextual cystine-addictions in VHL-deficient [clear cell] RCC is dependent on activating pre-existing oncogenic pathways to trigger programmed necrosis,” they concluded.

Dr. Chi suggests that targeting cancers for destruction by necrosis and not by apoptosis (most chemotherapy drugs kill cancer cells through apoptosis), holds great promise therapeutically. 

More than 100,000 people die of RCC each year, Dr. Chi noted.