Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics

Abstract

PP242, an inhibitor of mechanistic target of rapamycin (mTOR), displays potent anticancer effects against various cancer types. However, the underlying metabolic mechanism associated with the PP242 effects is not clearly understood. In this study, comprehensive metabolomics and lipidomics investigations were performed using ultra-high-performance chromatography-Orbitrap-mass spectrometry (UHPLC-Orbitrap-MS) in plasma and tumor tissue to reveal the metabolic mechanism of PP242 in an LS174T cell-induced colon cancer xenograft mouse model. After 3 weeks of PP242 treatment, a reduction in tumor size and weight was observed without any critical toxicities. According to results, metabolic changes due to the effects of PP242 were not significant in plasma. In contrast, metabolic changes in tumor tissues were very significant in the PP242-treated group compared to the xenograft control (XC) group, and revealed that energy and lipid metabolism were mainly altered by PP242 treatment like other cancer inhibitors. Additionally, in this study, it was discovered that not only TCA cycle but also fatty acid β-oxidation (β-FAO) for energy metabolism was inhibited and clear reduction in glycerophospholipid was observed. This study reveals new insights into the underlying anticancer mechanism of the dual mTOR inhibitor PP242, and could help further to facilitate the understanding of PP242 effects in the clinical application.

Liver Metabolic Dysregulation Induced by Polypropylene Nano- and Microplastics in Nile Tilapia Using Internal Extractive Electrospray Ionization Mass Spectrometry

“…PE is found predominantly within the mitochondrial membrane and is involved in cell proliferation and differentiation, as well as the possibility of cell apoptosis . The decrease in the PC/PE ratio will destroy the integrity of the hepatocyte and mitochondrial membrane, affect cell growth, and induce apoptosis …”

Identification of Key Pathways Involved in White Strain of Hypsizygus marmoreus Extracts-Induced Cell Death of Human Hepatoma Hep3B Cells by Next Generation Sequencing

“…Previous studies had demonstrated that the downregulation of PC and upregulation of lysoPC could induce cell apoptosis ( Anthony et al, 1999 ; Cui and Houweling, 2002 ; Takahashi et al, 2002 ). In the research of the antitumor effects of PP242, an inhibitor of mechanistic target of rapamycin (mTOR), in a colon cancer xenograft mouse model, Rashid et al (2020) indicated that lysoPC (18:2) in the PP242-treated mice was significantly increased after mTOR inhibition. It has also been suggested that lysoPC (16:0) induces apoptosis in human endothelial cells through a p38-MAPK-dependent pathway ( Takahashi et al, 2002 ).…”

Machine learning encodes urine and serum metabolic patterns for autoimmune disease discrimination, classification and metabolic dysregulation analysis

“…36–38 Furthermore, the down-regulation of phosphatidylethanolamine in disease groups caused disturbance to glycosylphosphatidylinositol (GPI)-anchor biosynthesis and glycerophospholipid metabolism, which could affect the integrity of the mitochondrial membrane, and cell proliferation, differentiation and apoptosis. 39–42…”