The tumor suppressor gene lkb1 is essential for glucose homeostasis during zebrafish early development

Abstract

The liver kinase B1 (LKB1) is encoded by tumor suppressor gene STK11, which is mutated in Peutz-Jeghers syndrome patients. Lkb1 plays indispensable roles in energy homeostasis. However, how Lkb1 regulates energy homeostasis in vivo remains to be fully understood. We found that inactivation of zebrafish Lkb1 upregulates pyruvate dehydrogenase kinase 2 expression and inactivates pyruvate dehydrogenase complex by increasing phosphorylation of pyruvate dehydrogenase. As a result, glycolysis is significantly enhanced as indicated by increased lactate production, which resembles the Warburg effect in cancer cells. Inhibition of Pdk2 in lkb1 mutants with dichloroacetate, a promising anticancer drug, rescued the lactate production to wild-type level, suggesting the lkb1 mutant may be used to screen compounds targeting aerobic glycolysis in cancer therapy.

Zebrafish Cancer Predisposition Models

“…Additionally, zebrafish lkb1 −/− mutant embryos have glucose homeostasis defects, enhanced glycolysis, and increased lactate production (Kuang et al, 2016). This is similar to the metabolic state observed in cancer cells which often rely on aerobic glycolysis and fermentation of pyruvate to lactate to produce ATP instead of oxidative phosphorylation.…”

“…This is termed the Warburg effect which, although inefficient for generating ATP, preserves carbon to support anabolic processes for increased proliferation (Vander Heiden et al, 2009). As a proof-of-principle, treatment with dichloroacetate, an aerobic glycolysis inhibitor, decreased lactate production in lkb1 −/− embryos, showing the potential of these mutants to be used as a drug screening platform to identify compounds that inhibit aerobic glycolysis (Kuang et al, 2016).…”

Accelerated loss of hypoxia response in zebrafish with familial Alzheimer’s disease-like mutation of Presenilin 1

“…Thus, PDK1 acts as a form of "rheostat" to set the relative rates of anaerobic glycolysis and oxidative phosphorylation. To determine the effects of age and the fAD-like alleles of psen1 on HIF1-directed responses to hypoxia, we used dqPCR to compare transcript levels from five HRGs: cd44a, edn1, igfbp3, mmp2 (reviewed in [34]) and pdk1 [35] in the brains of zebrafish exposed to normoxia or acute hypoxia.…”

Oncogenesis as a Selective Force: Adaptive Evolution in the Face of a Transmissible Cancer

“…Moreover, the low prevalence of DFTD in young devils may be attributed to juveniles rarely engaging in fights that result in bite wounds necessary for the transmission of DFTD . Additionally, young devils may potentially be protected by the expression of tumour suppressor genes that are required for proper chromosomal segregation in developing embryos . Due to the unique reproduction of marsupials (completing development in the pouch) the activity of these essential genes for early development may be sustained while the developing young occupy the pouch and thus protect them from cancer development .…”

“…[54,102,117] Additionally, young devils may potentially be protected by the expression of tumour suppressor genes that are required for proper chromosomal segregation in developing embryos. [118][119][120] Due to the unique reproduction of marsupials (completing development in the pouch) the activity of these essential genes for early development may be sustained while the developing young occupy the pouch and thus protect them from cancer development. [121] A final potential explanation for the appearance of DFTD in sexually mature devils could be due to a shift in resource allocation to mating and reproduction at the cost of continued tumour suppression.…”