One carbon metabolism in human lung cancer

Abstract

Background: Lung cancer remains the major cause of cancer related death worldwide. The discovery of targeted therapies against activating mutations in genes like EGFR considerably improved the prognosis for a subgroup of patients but still leaves a large part without a targeted therapy. One carbon metabolism (1CM) has been investigated in several cancer entities and its increased activity has been linked to higher tumor aggressiveness and reduced prognosis. In spite of 1CM enzymes role and correlation to cancer cells progression, comprehensive analysis for the diagnostic and functional role of the complete 1CM enzymes in lung cancer has not been conducted so far. Methods: We investigated the prognostic and functional relevance of five major 1CM factors (MTHFD2, PGDH3, SHMT2, MTHFD1 and TYMS) in the three major subclasses of lung cancer [pulmonary adenocarcinoma (AC), squamous cell lung cancer (SQCLC) and small cell lung cancer (SCLC)]. We analyzed 1CM enzymes expression and clinicopathological correlation in patient derived tissue samples of 103 AC, 183 SQCLC and 37 SCLC patients by immunohistochemistry. Furthermore, the effect of 1CM enzymes expression on lung cancer cell proliferation and the response to chemotherapy was investigated in 15 representative AC, SQCLC and SCLC cell lines.Results: Expression of MTHFD2 and PGDH3 was significantly correlated to a worse overall survival only in AC patients. Cell proliferation assays resolved that all 1CM enzymes have a significant impact on cell growth in AC cell lines and are partially involved in cell proliferation in SQCLC and SCLC cell lines. In addition, expression of MTHFD2 correlated significantly with an increased pemetrexed chemoresistance.Conclusions: Expression of MTHFD2 significantly reduces the prognosis of AC patients. Furthermore, MTHFD2 expression is crucial for survival of AC cell lines and its expression correlates with resistance against Pemetrexed. As MTHFD2 is almost not expressed in healthy adult tissue, we therefore suggest that the inhibition of MTHFD2 might be a potential therapeutic strategy to surround pemetrexed resistance in AC.

Regulation and Therapeutic Targeting of MTHFD2 and EZH2 in KRAS-Mutated Human Pulmonary Adenocarcinoma

“…Eighteen samples were KRAS-mutated (G12C n = 15, G12V n = 3) and 44 were found to be KRAS WT . The MTHFD2 statuses of the investigated samples were published previously [ 18 ] and can be found in Supplementary Table S1 . Comparing MTHFD2 expression in KRAS MUT and KRAS WT samples, we observed a significant correlation between high expression of MTHFD2 and KRAS MUT tumors ( p = 0.0066) ( Figure 1 a).…”

“…KRAS mutations play a vital role in controlling tumor metabolism, e.g., by stimulating glucose uptake [ 10 , 11 , 12 ], and an increased need for energy and elevated aerobic glycolysis are closely associated with chemoresistance, tumor progression, and metastasis of malignant tumors [ 13 , 14 , 15 , 16 ]. We and others have recently shown that KRAS mutations are connected to an enhanced dependency on one-carbon metabolism (1CM) in non-small cell lung cancer (NSCLC) and colorectal cancer [ 17 , 18 , 19 ]. One-carbon metabolism includes the methionine and folate cycles and is essential for the maintenance of cellular homeostasis.…”

“…In cancer cells, the high proliferation rate requires these one-carbon units for nucleotide synthesis, methylation, and reductive metabolism [ 20 ]. Furthermore, we have shown that Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is essential for the survival of NSCLC cell lines and is a prognostic factor in AC [ 18 ]. MTHFD2 is one of the key enzymes in 1CM and is strongly expressed in embryonic development but it is almost absent in most healthy adult tissues, making it a promising potential therapeutic target for cancer treatment [ 21 ].…”

“…MTHFD2 is one of the key enzymes in 1CM and is strongly expressed in embryonic development but it is almost absent in most healthy adult tissues, making it a promising potential therapeutic target for cancer treatment [ 21 ]. High levels of MTHFD2 have been associated with tumor recurrence and worse prognosis in multiple solid and liquid malignancies and participate in resistance against gemcitabine and pemetrexed [ 18 , 19 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

A Cluster of Metabolic-Related Genes Serve as Potential Prognostic Biomarkers for Renal Cell Carcinoma

“…MTHFD2 is also a metabolic checkpoint linking purine metabolism to autoimmune responses ( Sugiura et al, 2022 ). It is highly expressed in various cancers, playing a role in metabolic remodeling and regulating of the cell cycle in the mitochondria and nucleus, respectively ( Lee et al, 2021b ; Liu et al, 2021 ; Yao et al, 2021 ; Ren et al, 2022 ).…”