Serine Catabolism Regulates Mitochondrial Redox Control during Hypoxia

Abstract

The de novo synthesis of the non-essential amino acid serine is often upregulated in cancer. In this study we demonstrate that the serine catabolic enzyme, mitochondrial serine hydroxymethyltransferase (SHMT2) is induced when Myc-transformed cells are subjected to hypoxia. In mitochondria, SHMT2 can initiate the degradation of serine to CO2 and NH4+ resulting in net production of NADPH from NADP+. Knockdown of SHMT2 in Myc-dependent cells reduced cellular NADPH/NADP+ ratio, increased cellular reactive oxygen species (ROS) and triggered hypoxia-induced cell death. In vivo, SHMT2 suppression led to impaired tumor growth. In myc-amplified neuroblastoma patient samples, there was a significant correlation between SHMT2 and Hypoxia-inducible factor-1 α (HIF-1α) and SHMT2 expression correlated with unfavorable patient prognosis. Together these data demonstrate that mitochondrial serine catabolism supports tumor growth by maintaining mitochondrial redox balance and cell survival.

Targeting MTHFD2 in acute myeloid leukemia

“…However, we could not rescue the effects of MTH FD2 suppression in AML cell lines with the addition of up to 10 mM formate concentrations, a similar observation to that of Nilsson et al (2014). More recently, several publications supported the role of mitochondrial one-carbon metabolism in redox homeostasis and NAD PH production Ye et al, 2014). Fan et al (2014) demonstrated a decrease in the NAD PH/ NADP + ratio with MTH FD2 knockdown in HEK293T cells, and Ye et al (2014) demonstrated a decrease in the NAD PH/ NADP + ratio with SHMT2 knockdown only in hypoxic conditions in neuroblastoma cells Ye et al, 2014).…”

“…More recently, several publications supported the role of mitochondrial one-carbon metabolism in redox homeostasis and NAD PH production Ye et al, 2014). Fan et al (2014) demonstrated a decrease in the NAD PH/ NADP + ratio with MTH FD2 knockdown in HEK293T cells, and Ye et al (2014) demonstrated a decrease in the NAD PH/ NADP + ratio with SHMT2 knockdown only in hypoxic conditions in neuroblastoma cells Ye et al, 2014). Given that MTH FD2 is an NAD + dependent enzyme, we focused on measuring NAD + /NADH ratio in AML cells after MTH FD2 suppression and did not find a consistent difference in this ratio in the AML cell line setting (unpublished data), whereas samples with ssGSEA z-scores ≤−1 were labeled as significantly low enriched in the signature and highlighted blue.…”

“…We then performed ChIP-qPCR and confirmed this finding in AML cell lines. Previously, MYC has been implicated in controlling the one-carbon folate pathway, especially in the presence of hypoxia (Nikiforov et al, 2002;Ye et al, 2014), though this has not been previously studied in AML. In future studies, it may also be informative to perform metabolic profiling with MYC suppression by BET bromodomain inhibitors alone and in combination with MTH FD2-specific suppression.…”

Cancer, Oxidative Stress, and Metastasis

“…De novo serine synthesis and the folate pathway are another major source of NADPH for cancer cells Lewis et al 2014;Ye et al 2014). De novo serine synthesis can be limiting for flux through the folate pathway, and reduced serine hydroxymethyltransferase expression reduces the cellular NADPH/NADP þ ratio while increasing ROS levels and cell death .…”

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

“…It was reported recently that, upon serine starvation, p53 activates p21 to promote GSH production to combat ROS [25,26]. Additionally, p73, ATF4, G9A, HIF1 and PKCζ were also reported to regulate serine biosynthesis and metabolism [27][28][29][30][31]. However, compared to the profound understanding of glycolysis and glutaminolysis in cancer cells, we are only beginning to appreciate the critical impact of serine synthesis pathway (SSP) on cancer progression.…”