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.

Keywords: ALDH1L2; MTHFD2; SHMT2; folate pathway; one-carbon metabolism; pancreatic cancer.

Figure 1.

Schematic of one-carbon metabolism. Enzymes with polymorphisms investigated in the present study are illustrated in the boxes. ALDH1L1, aldehyde dehydrogenase 1 family member L1; ALDH1L2, aldehyde dehydrogenase 1 family member L2; AMT, aminomethyltransferase; CH2-THF, Methylenetetrahydrofolate; CHO-THF, formyl-tetrahydrofolate; DHFR, dehydrofolate reductase; MTHFD1, methylenetetrahydrofolate dehydrogenase D1; MTHFD2, methylenetetrahydrofolate dehydrogenase D2; HCHO, formaldehyde; NADPH, nicotinamide adenine dinucleotide phosphate; SHMT1, serine hydroxymethyltransferase 1; SHMT2, serine hydroxymethyltransferase 2; THF, tetrahydrofolate.

Figure 2.

Immunohistochemical analyses of MTHFD2, ALDH1L2 and SHMT2. Representative images of ALDH1L2, (A) score 0; (B) score 0; (C) score 2; (D) score 2. Representative images of MTHFD2, (E) score 0; (F) score 1; (G) score 2; (H) score 2. Representative images of SHMT2, (I), score 0; (J) score 1; (K), score 2; (L) score 2. Acini were used as positive controls. Scale bar, 100 µm. A, Acini; T, Tumors; ALDH1L2, aldehyde dehydrogenase 1 family member L2; MTHFD2, methylenetetrahydrofolate dehydrogenase D2; SHMT2, serine hydroxymethyltransferase 2.

Figure 3.

Kaplan-Meier estimator analysis. Associations between patient survival and (A) MTHFD2, (B) ALDH1L2 or (C) SHMT2 expression levels. MTHFD2, methylenetetrahydrofolate dehydrogenase D2; SHMT2, serine hydroxymethyltransferase 2; ALDH1L2, aldehyde dehydrogenase 1 family member L2.

Figure 4.

Associations between patient survival and the combined expression patterns of MTHFD2, ALDH1L2 and SHMT2. Associations between (A) OS or (B) DFS and triple low expression of MTHFD2, ALDH1L2 and SHMT2 (solid line; line 1); triple high expression of MTHFD2, ALDH1L2 and SHMT2 (dotted line, line 3); and other groups (broken line, line 2). Survival was estimated using Kaplan-Meier estimator analyses. P-values were calculated using the log-rank test. *P<0.001. MTHFD2, methylenetetrahydrofolate dehydrogenase D2; SHMT2, serine hydroxymethyltransferase 2; ALDH1L2, aldehyde dehydrogenase 1 family member L2; OS, overall survival; DFS, disease-free survival.