E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation

Abstract

Cell proliferation is known to be accompanied by activation of glycolysis. We have recently discovered that the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is degraded by the E3 ubiquitin ligase APC/C-Cdh1, which also degrades cell-cycle proteins. We now show in two different cell types (neoplastic and nonneoplastic) that both proliferation and aerobic glycolysis are prevented by overexpression of Cdh1 and enhanced by its silencing. Furthermore, we have coexpressed Cdh1 with PFKFB3-either wild-type or a mutant form resistant to ubiquitylation by APC/C-Cdh1-or with the glycolytic enzyme 6-phosphofructo-1-kinase and demonstrated that whereas glycolysis is essential for cell proliferation, its initiation in the presence of active Cdh1 does not result in proliferation. Our experiments indicate that the proliferative response, regardless of whether it occurs in normal or neoplastic cells, is dependent on a decrease in the activity of APC/ C-Cdh1, which activates both proliferation and glycolysis. These observations have implications for cell proliferation, neoplastic transformation, and the prevention and treatment of cancer.aerobic glycolysis | cell cycle | PFKFB3 | cancer

Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-β-TrCP, sequentially regulate glycolysis during the cell cycle

“…The function of this transient enhancement of glycolytic activity in late G1, which is necessary for cell cycle progression, now requires investigation because glycolysis might be used to generate energy, substrates for macromolecular synthesis, or for both purposes. Our present results obtained in a cancer-derived cell line, together with previous studies in a noncancer cell line (9) and in human T lymphocytes (10), suggest that these same, or similar, mechanisms underlie cell proliferation and enhanced metabolism in normal and neoplastic cells.…”

“…We have recently found that PFKFB3 is regulated during cell proliferation by APC/C-Cdh1 and that silencing this enzyme prevents cells from entering S phase (9,10). These findings suggest that there is close coordination between cell cycle progression and provision of the raw materials required for its completion.…”

Inhibition of Akt Potentiates 2-DG–Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia

“…Although there is substantial evidence to support increased glycolysis in tumor versus normal tissue, recently there have been reports indicating that glycolysis is closely linked with the cell cycle and that increased glucose metabolism is a consequence of growth signaling within a cell (normal or tumor) and not necessarily as a result of "rewiring" of a cancer cell (32). Nonetheless, increased glucose metabolism seems to be a hallmark of cancer, which is likely due to their uncontrolled and constant movement through the cell cycle as well as other factors associated with oncogenic transformation (30,33).…”

Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes

“…Inactivation of APC/C-Cdh1 enables PFKFB3 to up-regulate glycolysis, thus providing the cell with the glucose essential for the subsequent biosynthesis of macromolecules. Our previous studies (9) were carried out in two cell lines; we therefore decided to investigate whether the same mechanism operates in human proliferating primary cells.…”

“…Inactivation of APC/C-Cdh1 in G1 of the cell cycle is necessary for initiation of S phase, in which DNA is replicated and chromosomes are duplicated. We have recently found that APC/CCdh1 links cell cycle activity with that of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) (9,10). PFKFB3-a key regulator of glycolysis (11)-contains a KEN box motif and is thus also broken down by APC/C-Cdh1.…”