AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest

Abstract

Blocking mitotic progression has been proposed as an attractive therapeutic strategy to impair proliferation of tumour cells. However, how cells survive during prolonged mitotic arrest is not well understood. We show here that survival during mitotic arrest is affected by the special energetic requirements of mitotic cells. Prolonged mitotic arrest results in mitophagy-dependent loss of mitochondria, accompanied by reduced ATP levels and the activation of AMPK. Oxidative respiration is replaced by glycolysis owing to AMPK-dependent phosphorylation of PFKFB3 and increased production of this protein as a consequence of mitotic-specific translational activation of its mRNA. Induction of autophagy or inhibition of AMPK or PFKFB3 results in enhanced cell death in mitosis and improves the anti-tumoral efficiency of microtubule poisons in breast cancer cells. Thus, survival of mitotic-arrested cells is limited by their metabolic requirements, a feature with potential implications in cancer therapies aimed to impair mitosis or metabolism in tumour cells.

FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

“…9b shows, FR58P1a produces an increase in PINK1 levels. Consistent with mitophagy 52,53 , these TNBC cells also shown reduced mitochondrial OCR (Fig. 7g) with increased 2NBDG uptake (Fig.…”

Suppression of autophagy impedes glioblastoma development and induces senescence

“…18,26 A recent study suggests that maintaining glycolysis enhances cell survival during mitotic arrest induced by Cdc20 deletion. 27 This may imply that, in a similar fashion, the absence of glycolysis in autophagy-defective cells may contribute to their inability to proliferate when restimulated with full growth medium as observed in our system. It remains to be defined whether the role of autophagy in maintaining cell growth and metabolic activity is required for gliomagenesis in vivo.…”

Adipocyte-specific deletion of Ip6k1 reduces diet-induced obesity by enhancing AMPK-mediated thermogenesis

“…Conversely, immortalized MEFs from global Ip6k1 KO mice are reported to display higher glycolysis whereas oxygen consumption is compromised (55). AMPK stimulates glycolysis (28); thus it is feasible that increased AMPK in certain tissues may also enhance glycolytic energy metabolism. In conclusion, improved EE following adipocyte-specific Ip6k1 deletion or IP6K inhibition indicates that the pathway may have therapeutic potential in human obesity, T2D, and other metabolic diseases.…”

“…Accordingly, the plant-derived alkaloid berberine or microRNA-455 enhances brown adipogenesis via activation of AMPK (26,27). In addition, AMPK stimulates glycolysis (28) and coupled respiration-mediated ATP generation in metabolic tissues (29)(30)(31). Hence, the AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR) stimulates EE (32,33).…”