The mitochondrial one‑carbon metabolic pathway is associated with patient survival in pancreatic cancer

Abstract

The expression levels of one-carbon metabolic enzymes were investigated and observed to be correlated with clinicopathological parameters in patients with pancreatic cancer. Mitochondrial one-carbon metabolism comprises a network of biological reactions that integrate nutrient status with nucleotide synthesis, amino acid metabolism, antioxidant reduced nicotinamide adenine dinucleotide phosphate production and epigenetic methylation processes. Previous studies have reported that the hyper-activation of mitochondrial one-carbon metabolism serves a significant role in malignant cancer phenotypes. A total of 103 patients underwent surgical resection of pancreatic ductal adenocarcinomas (PDAC) at Osaka University Hospital between April 2007 and December 2013 and were enrolled in this study. Subsequently, the expression of the one-carbon metabolic enzymes methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), aldehyde dehydrogenase 1 family member L2 (ALDH1L2), and serine hydroxymethyltransferase (SHMT2) was examined using immunohistochemical analysis. The immunohistochemical analyses demonstrated that patients with high expression levels of MTHFD2, ALDH1L2 or SHMT2 had significantly poor overall survival (OS) and disease-free survival (DFS) rates, as compared with patients with low expression levels. Furthermore, multivariate Cox proportional hazards analysis indicated that MTHFD2 and ALDH1L2 were independent prognostic factors for OS and DFS, whereas SHMT2 was not predictive of DFS. However, high and low expression levels of all three folate metabolic enzymes were significantly associated with improved OS and DFS, compared with the high expression of one or two folate metabolic enzymes. The expression levels of mitochondrial one-carbon metabolic enzymes are independent prognostic factors and potential therapeutic targets for future pancreatic cancer treatments.

NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications

“…81,82 Nevertheless, ALDH1L2 is highly expressed and presents as an independent prognostic factor for overall survival in melanoma, PDAC, and CRC. 77,78,83 Depletion of ALDH1L2 markedly decreases the NADPH/NADP + and GSH/GSSG ratios, reduces the circulating tumor cells in blood and alleviates the metastatic burden. 77,83,84 In addition, the expression of ALDH1L2 is upregulated by some certain drugs, such as thapsigargin and tunicamycin, endoplasmic reticulum stress inducers in immortalized human B cells, 85 mitotane, an adjuvant monotherapy used for treating adrenocortical carcinoma, 86 and the indomethacin, an anti-inflammatory agent in breast cancer cells.…”

“…77,78,83 Depletion of ALDH1L2 markedly decreases the NADPH/NADP + and GSH/GSSG ratios, reduces the circulating tumor cells in blood and alleviates the metastatic burden. 77,83,84 In addition, the expression of ALDH1L2 is upregulated by some certain drugs, such as thapsigargin and tunicamycin, endoplasmic reticulum stress inducers in immortalized human B cells, 85 mitotane, an adjuvant monotherapy used for treating adrenocortical carcinoma, 86 and the indomethacin, an anti-inflammatory agent in breast cancer cells. 87 Thus, further exploration of the association between the effects of these drugs on the ALDH1L2 expression and the cellular response to redox stress is needed.…”

The complexity of the serine glycine one-carbon pathway in cancer

“…Other enzymes of the SGOCP play a key role in tumorigenesis. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is consistently up-regulated in many cancer types, and its expression significantly correlates with poor clinical outcome in breast cancer, pancreatic carcinomas, renal cell carcinoma, and leukemia and in a particularly aggressive metabolic subtype of hepatocellular carcinoma (HCC; Bidkhori et al, 2018;Lehtinen et al, 2013;Lin et al, 2018;Liu et al, 2014;Nilsson et al, 2014;Noguchi et al, 2018;Reina-Campos et al, 2019;Tedeschi et al, 2015). MTHFD2 is a dual-action enzyme (dehydrogenase and cyclohydrolase) that catalyzes the reversible conversion of 5,10methylene-THF into 10-formyl-THF in the mitochondria, while MTHFD1, its cytosolic counterpart, catalyzes an extra reaction (synthetase) to convert 10-formyl-THF into THF and formate ( Fig.…”

Cancer proteome and metabolite changes linked to SHMT2

“…Serine catabolism by SHMT2 has been shown to affect complex I protein expression by epigenetic regulation of DNA methylation [14] and mitochondrial tRNA [15,16]. These studies used inhibitors [13] or SHMT2 knock out methods [14,15,17] to impair SHMT2 function in cells. Our data showed that over-expression of SHMT2, a phenomenon seen in tumors, reduced ETC protein expression.…”