Integrative Proteomic and Pharmacological Analysis of Colon Cancer Reveals the Classical Lipogenic Pathway with Prognostic and Therapeutic Opportunities

Abstract

Despite recent advancements, the high mortality rate remains a concern in colon cancer (CAC). Identification of therapeutic markers could prove to be a great asset in CAC management. Multiple studies have reported hyperactivation of de novo lipogenesis (DNL), but its association with the pathology is unclear. This study aims to establish the importance as well as the prognostic and therapeutic potential of DNL in CAC. The key lipogenic enzymes fatty acid synthase along with ATP citrate lyase were quantified using an LC–MS/MS-based targeted proteomics approach in the samples along with the matched controls. The potential capacity of the proteins to distinguish between the tumor and controls was demonstrated using random forest-based class prediction analysis using the peptide intensities. Furthermore, in-depth proteomics of DNL inhibition in the CAC cell line revealed the significance of the pathway in proliferation and metastasis. DNL inhibition affected the major signaling pathways, including DNA repair, PI3K–AKT–mTOR pathway, membrane trafficking, proteasome, etc. The study revealed the upregulation of 26S proteasome machinery as a result of the treatment with subsequent induction of apoptosis. Again, in silico molecular docking-based drug repurposing was performed to find potential drug candidates. Furthermore, we have demonstrated that blocking DNL could be explored as a therapeutic option in CAC treatment.

Lipidomics Profiling Reveals Differential Alterations after FAS Inhibition in 3D Colon Cancer Cell Culture Models

“…It is observed in both HCT 116 and HT-29 spheroids that cerulenin treatments decrease very long chain lipids (54 or more total carbons) but have an increase in medium-length lipids (34–36 total carbons). 2D HCT 116 cells exposed to cerulenin have downregulation of HACD3, an enzyme responsible for the generation of very long chain fatty acids (VLCFAs) . This previous observation corroborates with the presented lipidomics data showing that cerulenin treatments have downregulation of these very long chain lipids (Figure A).…”

“…2D HCT 116 cells exposed to cerulenin have downregulation of HACD3, an enzyme responsible for the generation of very long chain fatty acids (VLCFAs). 59 This previous observation corroborates with the presented lipidomics data showing that cerulenin treatments have downregulation of these very long chain lipids (Figure 2A).…”

“…The lower number of MUFAs and PUFAs in cerulenin treatments suggest a different cell death mechanism occurs with the generation 1 inhibitor. A recent study from Barpanda et al observed that 2D HCT 116 cells exposed to cerulenin have upregulation of PSMC5, PSMC4, and RPS27A, proteins that are critical in the Ub-proteasome machinery . Upregulation of the Ub-proteasome machinery indicates that these cells are dying via apoptosis.…”

The 2023 Report on the Proteome from the HUPO Human Proteome Project

“…Proteomics can aid such studies. 63,64 Mass cytometry characterized the single-cell signaling profiles of 62 breast cancer cell lines and five healthy controls and accurately predicted drug sensitivity. 65…”

“…Drug repurposing is increasingly becoming an attractive proposition since it may lower overall development costs and shorten development timelines, especially if drug safety has already been established. Proteomics can aid such studies. , Mass cytometry characterized the single-cell signaling profiles of 62 breast cancer cell lines and five healthy controls and accurately predicted drug sensitivity …”