Redox homeostasis of one-carbon metabolism-dependent reprogramming is critical for RCC progression under exogenous serine/glycine-deprived conditions.

Background: Serine/glycine are critical for the growth and survival of cancer cells. Some cancer cells are more dependent on exogenous serine/glycine than endogenously synthesized serine/glycine. However, the function and underlying mechanisms of exogenous serine/glycine in renal cell carcinoma (RCC) remain unclear.

Methods: We conducted a comprehensive assessment of RCC progression under conditions of exogenous serine/glycine deprivation and explored the underlying mechanism via immunofluorescence, autophagic flux analysis, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) measurements.

Results: The expression of the serine synthesis pathway enzymes was decreased in RCC specimens, the de novo serine synthesis pathway (SSP) was reduced in RCC. And the levels of endogenously synthesized serine/glycine were little. Yet, the exogenous serine/glycine deprivation significantly inhibited the growth of RCC cells both in vitro and in vivo, indicating that exogenous serine/glycine were important for RCC progression. Mechanistically, the deprivation of exogenous serine/glycine disrupted one-carbon metabolism and increased the ratio of NAD(P)/NAD(P)H, resulting in the accumulation of reactive oxygen species (ROS) and oxidative stress, which induced autophagic flux and enhanced lysosome membrane permeabilization (LMP), leading to the release of lysosomal cathepsins into the cytoplasm, which ultimately triggered lysosomal dependent cell death (LDCD) and inhibited the progression of RCC.

Conclusions: Our results indicate that exogenous serine/glycine are critical for RCC progression by maintaining one-carbon metabolism-dependent redox homeostasis, which provides new insights for the development of dietary serine/glycine starvation-based therapeutic approaches for RCC.