Effects and mechanisms of fatty acid metabolism‑mediated glycolysis regulated by betulinic acid‑loaded nanoliposomes in colorectal cancer

Abstract

Although previous studies have demonstrated that triterpenoids, such as betulinic acid (BA), can inhibit tumor cell growth, their potential targets in colorectal cancer (CRC) metabolism have not been systematically investigated. In the present study, BA-loaded nanoliposomes (BA-NLs) were prepared, and their effects on CRC cell lines were evaluated. The aim of the present study was to determine the anticancer mechanisms of action of BA-NLs in fatty acid metabolism-mediated glycolysis, and investigate the role of key targets, such as acyl-CoA synthetase (ACSL), carnitine palmitoyltransferase (CPT) and acetyl CoA, in promoting glycolysis, which is activated by inducing hexokinase (HK), phosphofructokinase-1 (PFK-1), phosphoenolpyruvate (PEP) and pyruvate kinase (PK) expression. The results demonstrated that BA-NLs significantly suppressed the proliferation and glucose uptake of CRC cells by regulating potential glycolysis and fatty acid metabolism targets and pathways, which forms the basis of the anti-CRC function of BA-NLs. Moreover, the effects of BA-NLs were further validated by demonstrating that the key targets of HK2, PFK-1, PEP and PK isoenzyme M2 (PKM2) in glycolysis, and of ACSL1, CPT1a and PEP in fatty acid metabolism, were blocked by BA-NLs, which play key roles in the inhibition of glycolysis and fatty acid-mediated production of pyruvate and lactate. The results of the present study may provide a deeper understanding supporting the hypothesis that liposomal BA may regulate alternative metabolic pathways implicated in CRC adjuvant therapy.

Assessment of Betulinic Acid Cytotoxicity and Mitochondrial Metabolism Impairment in a Human Melanoma Cell Line

“…In the present study, we analyzed the BA effects on human melanoma cells using the Seahorse XFe24 extracellular flux analyzer and showed the dose-dependent inhibition of both mitochondrial respiration and glycolysis. Our data are in line with a recent study demonstrating that citrate synthase activity, glycolysis rate and carbon flux through the TCA cycle were inhibited in BA-loaded nanoliposomes-treated colorectal cancer cells; the results were confirmed by the glycolysis stress test in which ECAR values revealed that both the basal glycolysis and the maximum glycolytic capacity were reduced by BA-loaded nanoliposomes [ 34 ].…”

Integrative analysis of PTEN‐related hub genes and validating drug targets for colorectal cancer

“…However, the role of PLCB4 in OXA resistance requires further studies for verification. [38][39][40][41][42][43] STC2 is implicated in glucose homeostasis, phosphorus metabolism, and various malignancies. Studies have consistently reported higher STC2 levels in CRC tissues compared to normal tissues, with correlations observed with tumor size, histological grade, lymph node metastasis, lymphatic invasion, and tumor depth.…”

“…In CRC, downregulation of PLCB4 is associated with oxaliplatin (OXA) resistance. However, the role of PLCB4 in OXA resistance requires further studies for verification 38–43 …”

Role of glycolysis in inflammatory bowel disease and its associated colorectal cancer

“…Parthenolide derivatives reduce PKM2 expression in CRC cells, inhibit the PKM2/STAT3 signaling pathway, and PKM2 dimerization in nuclear translocation, inhibiting CRC tumor growth ( 149 ). Betulinic acid (BA) inhibits the glycolytic enzymes (HK2/FK1/PEP/PKM2) in CRC cells ( 150 ). Moreover, Atractylenolide I downregulates HK2 expression and blocks the JAK2/STAT3 pathway in CRC cells, inducing cellular regulation and alleviating CRC ( 151 ).…”