A key role for transketolase-like 1 in tumor metabolic reprogramming

Abstract

Metabolic reprogramming, a crucial cancer hallmark, shifts metabolic pathways such as glycolysis, tricarboxylic acid cycle or lipogenesis, to enable the growth characteristics of cancer cells. Here, we provide evidence that transketolase-like 1 (TKTL1) orchestrates aerobic glycolysis, fatty acid and nucleic acid synthesis, glutamine metabolism, protection against oxidative stress and cell proliferation. Furthermore, silencing of TKTL1 reduced the levels of sphingolipids such as lactosylceramide (a sphingolipid regulating cell survival, proliferation and angiogenesis) and phosphatidylinositol (which activates PI3K/Akt/mTOR signaling). Thus, in addition to its well-known roles in glucose and amino acid metabolism, TKTL1 also regulates lipid metabolism. In conclusion, our study provides unprecedented evidence that TKTL1 plays central roles in major metabolic processes subject to reprogramming in cancer cells and thus identifies TKTL1 as a promising target for new anti-cancer therapies.

Tumor-associated metabolic and inflammatory responses in early stage non-small cell lung cancer: Local patterns and prognostic significance

“…Dietary studies have also indicated that the inhibition of the PPP minimizes tumor growth [13,36,37]. Although it has been reported that TKTL1 contributes to total transketolase activity [38], with a similar metabolic role to TKT, this protein also seems to participate in other metabolic processes such as DNA hypomethylation, fatty acid synthesis, and even the one-substrate reaction catalyzing the transformation of xylulose-5-phosphate into glyceraldehyde-3-phosphate and acetate [39,40]. To our knowledge, this is the first time that different patterns of expression in TKT and TKTL1 in NSCLC progression have been shown in the same tissue samples.…”

Resveratrol Inhibits Expression of Cancer-Specific Pentose Phosphate Pathway Enzyme Tktl1

“…This study for the first time shows that resveratrol directly inhibits mRNA and protein levels of TKTL1. TKTL1 is an enzyme known to promote nucleotide synthesis by providing the precursor molecule ribose-5-phosphate [19]. Metabolic reprogramming and increased glucose utilization, leading to Warburg effect is hallmark of cancer cells [20].…”

Review of metabolic pathways activated in cancer cells as determined through isotopic labeling and network analysis

“…Recent work suggests that the enzyme transketolase-like 1 (TKTL1) may resemble its bacterial counterpart phosphoketolase (Heath et al, 1958) (Schramm et al, 1958) in terms of its capability of cleaving xylulose-5-phosphate into GAP and acetate (Diaz-Moralli et al, 2016). GAP is diverted back to glycolysis while acetate can be utilized to replenish acetyl-CoA for lipid synthesis.…”

“…With these quantitative results, the authors concluded that acetate is the dominant source of labeling for acetyl-CoA under hypoxic conditions (Kamphorst et al, 2014) (Mashimo et al, 2014). In addition, the TKTL1 activity was suggested through a 1,2- 13 C 2 -glucose labeling experiment in which the labeling pattern of lactate was altered following genetic knockdown in a manner consistent with the presence of the cleavage reaction catalyzed by TKTL1 (Diaz-Moralli et al, 2016). …”