Metabolism and proliferation share common regulatory pathways in cancer cells

Abstract

Cancer development involves major alterations in cells' metabolism. Enhanced glycolysis and de novo fatty acids synthesis are indeed characteristic features of cancer. Cell proliferation and metabolism are tightly linked cellular processes. Others and we have previously shown a close relationship between metabolic responses and proliferative stimuli. In addition to trigger proliferative and survival signaling pathways, most oncoproteins also trigger metabolic changes to transform the cell. We present herein the view that participation of cell-cycle regulators and oncogenic proteins to cancer development extend beyond the control of cell proliferation, and discuss how these new functions may be implicated in metabolic alterations concomitant to the pathogenesis of human cancers.

Figure 1. Cross-talk between glycolysis and de novo FA synthesis in cancer cells

This model highlights the main differences in glucose and fatty acids utilization between quiescent (A) and highly proliferative cells (B). Red arrows indicate preferred metabolic pathway. In non-proliferating cells glucose can either be used for glycogen or fatty acids synthesis, or can be converted to pyruvate through basal rate of glycolysis that occurs in the cytoplasm. Pyruvate is then imported into the mitochondrion where it is decarboxylated to acetyl Coa or oxalacetate (OAA). Circulating fatty acids are also imported into non-proliferating cells were they are stored as triglycerides or oxidized into the mitochondrion to generate acetyl-CoA. Acetyl-CoA derived from both glucose and fatty acids is then oxidized through TCA cycle that produces intermediate citrate that is directed toward mitochondrial OXPHOS to generate ATP. In contrast, in proliferative cancer cells, the glycolytic flux is largely increased and most of the imported glucose is converted to the glycolytic end-product, pyruvate. The resulting pyruvate is mainly converted to lactate which is secreted from the cells, whereas the remaining pyruvate is converted to acetyl-CoA, which in turn is directed toward de novo FA synthesis. Circulating fatty acids are also mainly oxidized to generate acetyl-CoA. Acetyl-CoA derived from both glucose and fatty acids is then oxidized through TCA cycle to produced intermediate citrate. The resulting citrate is not directed toward OXPHOS but rather is exported to the cytoplasm where it is re-converted to acetyl-CoA, which, in turn, is used for de novo fatty acids biosynthesis. Abbreviations: Glc, glucose; FA, fatty acids; OAA, oxaloacetate; TCA, tricarboxylic acid; OXPHOS, oxidative phosphorylation.

Figure 2. Oncogenic regulatory pathways in the control of the cancer cells metabolism

This scheme represents the main implications of oncogenic pathways (in red) in the regulation of glycolysis and de novo lipogenesis in cancer cells. Metabolic effects of the PI3K/Akt, Ras and c-Myc oncogenic pathways include enhanced glucose uptake through increased surface expression of glucose transporter. Hence, they enhance the glycolytic flux, including lactate production, by stimulating glycolytic enzymes activity. Moreover, both Akt and Ras signaling promote de novo FA synthesis through increased SREBP-1 mediated transcription of lipogenic enzymes, and direct stimulation of ACL activity by Akt channels glucose-derived metabolites towards de novo FA biosynthesis. In cooperation with E2F1, c-Myc promotes the transcription of enzymes necessary to support nucleotides biosynthesis from intermediates of the glycolysis. In the case of p53 or PTEN tumor suppressors (in blue), loss of function mutations in cancer cells has the opposite of the effects shown here. Abbreviations: Glc, Glucose; HK, hexokinase; Glc-6-P, glucose-6-phosphate; 3-PG, 3-phosphoglycerate; GF, growth factors; PI3K, phosphatidylinositol 3-Kinase; PIP₃, phosphatidylinositol tri-phosphate; PTEN, phosphatase and tensin homolog; MAPK, mitogen-activated protein kinase; SREBP, sterol regulatory element-binding protein; LDH-A, lactate dehydrogenase-A; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; OAA, oxaloacetate; ACL, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; FA, fatty acids; TCA, tricarboxylicacid; OXPHOS, oxidative phosphorylation

Figure 3. Dual role for the E2F pathway in the control of both cell proliferation and the metabolic response

In response to proliferative stimuli such as insulin, glucose and nutrients, the cyclin/cdk4 complex is activated and phosphorylates the retinoblastoma protein pRB, which represses transcription when associated with E2F transcription factors. Activated E2F1 stimulates the expression of target genes implicated in cell cycle progression (blue circle). In addition, E2F1 triggers an adapted metabolic transcriptional response, depending on the cell type. In beta cells, E2F1 will stimulate the expression of Kir6.2, thus facilitating insulin secretion. In other cell types, such as muscle or cancer cells E2F1 facilitates glycolysis and represses, by still unknown mechanisms oxidative phosphorylation. This coordinated response is essential to sustain normal proliferation and development. It is conceivable that changes in this coordinated response might lead to abnormal metabolic changes during tumor development and cancer progression. Abbreviations: OXPHOS, oxidative phosphorylation.