Cancer Metabolism: Fasting Reset, the Keto-Paradox and Drugs for Undoing

Abstract

In tumor cells, ketolysis “via” succinyl-CoA: 3-oxoacid-CoAtransferase (SCOT) and acetyl-CoA acetyltransferase 1 (ACAT1) is a major source of mitochondrial acetyl-CoA. Active ACAT1 tetramers stabilize by tyrosine phosphorylation, which facilitates the SCOT reaction and ketolysis. Tyrosine phosphorylation of pyruvate kinase PK M2 has the opposite effect, stabilizing inactive dimers, while pyruvate dehydrogenase (PDH), which is already inhibited by phosphorylation, is acetylated by ACAT1 and is doubly locked. This closes the glycolytic supply of acetyl-CoA. In addition, since tumor cells must synthesize fatty acids to create new membranes, they automatically turn off the degradation of fatty acids into acetyl-CoA (“via” the malonyl-CoA brake for the fatty acid carnityl transporter). Thus, inhibiting SCOT the specific ketolytic enzyme and ACAT1 should hold back tumor progression. However, tumor cells are still able to take up external acetate and convert it into acetyl-CoA in their cytosol “via” an acetyl-CoA synthetase, which feeds the lipogenic pathway; additionally, inhibiting this enzyme would make it difficult for tumor cells to form new lipid membrane and survive.

Hacking the Lipidome: New Ferroptosis Strategies in Cancer Therapy

“…The final source is from exogenous acetate (catalyzed by acetyl-CoA synthase (ACS)). Authors [ 126 ] have proposed to inactivate the latter pathway using allicine or orotate. In contrast to normal cells, in cancer cells, all three of these sources are unavailable, and only ketolysis is a viable pathway for acetyl-CoA production.…”

“…M. Israel et al provided an in-depth explanation of the role of ketolysis in cancer progression and the anticancer mechanisms of ketolysis inhibitors [ 126 ].…”

“…This is because other sources of acetyl-CoA, such as the Krebs cycle and fatty acid β-oxidation, are inhibited in cancer cells. Normal cells are safe during the inhibition of ketolysis because they have alternative open sources of acetyl-CoA [ 75 , 76 , 126 , 127 ].…”

“…Compounds-inhibitors of de novo lipogenesis and ketolysis are presented in Table 4. SCOT-ACAT1 (i) 3-alpha R lipoic acid natural potential [126,127] SCOT-ACAT1 (i) hydroxycitrate (from Garcinia Cambogia); natural potential [126,127] SCOT-ACAT1 (i) ACS (i) allicin natural potential [126,127] * (i) inhibitor.…”

Glutathione-Responsive Organosilica Hybrid Nanosystems for Targeted Dual-Starvation Therapy in Luminal Breast Cancer

“…In recent years, the metabolic reprogramming of tumor cells has been identified as one of the 10 key biological characteristics of tumors . While normal cells primarily rely on aerobic glycolysis as their main energy supply pathway, tumor cells exhibit a preference for anaerobic glycolysis (known as the Warburg effect) in order to meet their high energy demands for vigorous metabolism and abnormal proliferation while minimizing energy consumption. − The anaerobic glycolysis process in cancer cells generates a higher amount of adenosine triphosphate (ATP) per unit time and produces essential substances such as amino acids, nucleotides, and lipids necessary for tumor growth. − Additionally, certain tumors exhibit abnormal activation of lipid metabolism pathways to contribute to cellular energy supply . For instance, several cancer types, including prostate cancer, hepatocellular carcinoma, ovarian cancer, and triple-negative breast cancer, display heightened activity in fatty acid oxidation (FAO). − The combined effect of anaerobic glycolysis and lipid metabolism allows tumors to utilize various nutrients for energy supply and enhances the adaptability of tumor cells to their microenvironment .…”