Targeting Pyruvate Kinase M2 and Hexokinase II, Pachymic Acid Impairs Glucose Metabolism and Induces Mitochondrial Apoptosis

Abstract

Pachymic acid (PA), a triterpenoid from Poria cocos, has various pharmacological effects, including anti-inflammatory, anti-cancer, anti-aging, and insulin-like properties. PA has gained considerable research attention, but the mechanism of its anti-cancer effects remains unclear. In this study, pyruvate kinase M2 (PKM2) was discovered as a PA target via the drug affinity responsive target stability. Molecular docking and enzyme assay revealed that PA is a competing activator of PKM2, and mimics the natural activator, fructose-1,6-bisphosphate. PKM2 activation should augment the flux of glycolysis. However, decreased glucose uptake and lactate production after PA treatment was observed in SK-BR-3 breast carcinoma cells, indicating a blockage or downregulation of glycolysis. The potential of previously reported triterpenoids in blocking hexokinase II (HK2) activity inspired us to investigate the inhibition effect of PA on HK2 activity. Molecular docking and enzyme assay confirmed that PA was an inhibitor of HK2, with an IC 50 of 5.01 µM. The possible consequences of glycometabolic regulation by PA, such as dissociation of HK2 from the mitochondria, release of mitochondrial cytochrome (Cyt) c, depletion of ATP, and generation of reactive oxygen species, were further validated. Furthermore, the details of the possible linkage of targeting PKM2 and HK2 with previously reported actions of PA were discussed. The results of our study provided valuable information on the anti-cancer mechanisms of PA.

Signaling, metabolism, and cancer: An important relationship for therapeutic intervention

“…Some of these studies emphasize targeting the metabolism. For example, studies have indicated that targeting HK2and PKm2 with phachymic acid can weaken glycolysis and induce apoptosis (Miao et al, 2019). In previous sections, we dealt with the anito‐apoptotic role of hexokinase 2.…”

“…In previous sections, we dealt with the anito‐apoptotic role of hexokinase 2. Therefore, it is possible that phachymic acid may be able to induce apoptosis through mechanisms such as separating HK2 from the mitochondrial membrane (Miao et al, 2019; Xue et al, 2019). In addition, phachymic acid can increase the expression of PTEN and attenuate AKT/PI3K signaling pathway in cancer cells (Wen et al, 2018).…”

Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

“…Pachymic acid, a lanostane-type triterpenoid from Poria cocos, could bind PKM2 in the pocket of its natural activator, fructose-1,6-bisphosphate and block the glycolysis of breast cancer cells. Additionally, pachymic acid is also an inhibitor of HKII [41].…”

Phytochemistry and Pharmacological Activities of Wolfiporia cocos (F.A. Wolf) Ryvarden & Gilb

“…Both compound 33 and 38 had a cytotoxicity effect on Molt 4 and HL 60 leukemic cell lines and targeting other than topoisomerases may be involved in the anti-proliferative activity (Lai et al, 2016). Compound 1 was discovered as a competing activator of PKM2, leading to a decreasing glucose uptake and lactate production in SK-BR-3 breast carcinoma cells, indicating that glycolysis was blocked or down-regulated to induce tumor cell proliferation (Miao et al, 2019). The results showed that compound 1 had markedly inhibition efficiency on human primary osteosarcoma cells proliferation concentration-and time-dependently.…”