Malic enzyme 1 (ME1) in the biology of cancer: it is not just intermediary metabolism

Abstract

Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine. Multiple studies have since documented that ME1 is pro-oncogenic in numerous epithelial cancers. In tumor cells, the reduction of ME1 gene expression or the inhibition of its activity resulted in decreases in proliferation, epithelial-to-mesenchymal transition and in vitro migration, and conversely, in promotion of oxidative stress, apoptosis and/or cellular senescence. Here, we integrate recent findings to highlight ME1’s role in oncogenesis, provide a rationale for its nexus with metabolic syndrome and diabetes, and raise the prospects of targeting the cytosolic NADPH network to improve therapeutic approaches against multiple cancers.

Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions

“…On the other hand, it is reported that G6PD is not essential for K-Ras-driven tumors growth or metastasis [ 65 ], suggesting a less dependence on oxPPP of solid tumors in the context of glucose-deficient TME. Furthermore, the expression of IDH1 in prostate tumors and the expression of ME1 in gastric/colon/rectal/cancers were reported to be higher than adjacent non-tumor tissues [ 17 , 66 ]. Consequently, tumors possibly depend on IDH1 and ME1 more than adjacent non-tumor tissues, resulting in a therapeutic liability that can be exploited by targeting both IDH1 and ME1.…”

“…ME1 is reported to regulate NADPH homeostasis to promote cancer growth and metastasis in gastric cancer [ 15 ] and nasopharyngeal carcinoma [ 16 ]. ME1 is found to be co-expressed with IDH1 and G6PD in diverse cancer cell lines [ 17 ], and ME1 can collaborate with mitochondrial IDH2 to maintain antioxidant systems to support tumor growth and metastasis [ 18 ]. Folate-dependent NADPH production by MTHFD and ALDH1L also contributes a large proportion to total NADPH pool in proliferating cells [ 10 ].…”

Expression of Lipid-Metabolism Genes Is Correlated With Immune Microenvironment and Predicts Prognosis in Osteosarcoma

“…ME1 encodes malic enzyme 1 (ME1), which catalyzes the transformation of malate to pyruvate and promotes the formation of NADPH concomitantly. Prior studies reported that ME1 mediated the lipid metabolism through participating in lipid biosynthesis basically (Simmen et al, 2020). Numerous researches have provided the evidence of the pro-oncogenic role of ME1 in multiple tumors (Simmen et al, 2020).…”

“…Prior studies reported that ME1 mediated the lipid metabolism through participating in lipid biosynthesis basically (Simmen et al, 2020). Numerous researches have provided the evidence of the pro-oncogenic role of ME1 in multiple tumors (Simmen et al, 2020). ALOX15B (Arachidonate 15-Lipoxygenase Type B) has been demonstrated as risk genes in colorectal cancer and lung squamous cell carcinoma (Yuan et al, 2020;Kim et al, 2021).…”

Metabolic response to radiation therapy in cancer

“…It is possible therefore that the activation of the NRF2 pathway by radiation 129 contributes to increased lactate production by upregulating malic enzyme activity. The conversion of malate to pyruvate by malic enzymes generates NADPH, thus further contributing to antioxidant defenses, as well as to lipid and cholesterol biosynthesis 154 …”