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Metabolomic analysis of colorectal cancer cells using mass spectrometry

ABSTRACT: Colorectal cancer (CRC) is one of the most prevalent tumors, with a high mortality rate. Nearly half of CRC patients develop metastasis, which accounts for as many as 90% of CRC-related deaths. In the metastasis process, cancer cells exhibit altered dependency on specific metabolic pathways and some of the metabolites discovered might be useful as potential diagnostic biomarkers. To identify metabolic pathway dependencies in CRC metastasis, mass spectrometry-based untargeted metabolomic analysis was performed in two pairs of CRC cell lines with different metastatic abilities. Each pair of cell lines was comprised of primary and metastatic colorectal cancer cell lines (SW480 vs. SW620; HT-29 vs. COLO 205). Relative levels of intracellular metabolites distinguished high-metastatic CRC cells from low-metastatic CRC cells.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Cancer

SUBMITTER: Wenjun Zhang

PROVIDER: ST002341 | MetabolomicsWorkbench | Thu Oct 06 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Colorectal cancer (CRC) is one of the most lethal cancers when it progresses to the advanced/metastatic stage. Treatment options for refractory metastatic colorectal cancer (mCRC) are limited. Therefore, there is an urgent need to develop effective treatment methods for metastatic colorectal cancer. In this study, we screened a library of small molecules for inhibitors of CRC recurrence using CRC cell lines and patient-derived organoids (PDOs) from metastatic, heavily pretreated CRC. The in vivo efficacy of LS-1-2 was evaluated in the HCT116 and the resistant HCT8 cell lines, patient-derived xenografts(PDXs) including refractory mCRC, and a liver metastasis mouse model. Biotin pull-down and liquid chromatography tandem-mass spectrometry (LC-MS/MS) were performed to identify proteins that interact with LS-1-2. The genome-wide gene expression and quantitative phosphoproteomic analyses were performed to determine the signaling pathway involved in LS-1-2. Molecular docking, molecular dynamics analysis and cellular thermal shift assays were used to predict and validate the binding sites of LS-1-2 on non-muscle Myosin IIA (NMHC IIA). Our results showed that LS-1-2 exhibited broad antiproliferative effects on a series of CRC cell lines and PDOs. The in vivo anti-tumor efficacy of LS-1-2 was demonstrated across cell line- and patient-derived xenografts and in the liver metastatic CRC model. NMHC IIA was identified as a direct target of LS-1-2, and LS-1-2 competitively inhibited the phosphorylation of NMHC IIA at S1943 and S1714 by CK2. NMHC IIA phosphorylation promoted CRC cell proliferation and invasion, which was reduced by LS-1-2. NMHC IIA phosphorylation-mediated YAP activity induced activation of AKT and inactivation of FOXO3a and was suppressed by LS-1-2. In conclusion, our findings suggest that NMHC IIA phosphorylation can be used as a potential molecular target in CRC metastasis, and that targeting NMHC IIA phosphorylation by LS-1-2 may be a promising strategy for the treatment and prevention of CRC metastasis.

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Metabolomic analysis of colorectal cancer cells using mass spectrometry

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