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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.

SUBMITTER: Wang G

PROVIDER: S-EPMC7640364 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Wang Gang G Yu Yang Y Wang Yu-Zhu YZ Zhu Zhi-Min ZM Yin Pei-Hao PH Xu Ke K

Oncology reports 20201001 6

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 investi ...[more]

PMID: 33125108

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Project description:Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids' synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

Dataset Information

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

Publications

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

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