Phosphatidylcholine and CHPT1 as Central Drivers of Chemoresistance in Colorectal Cancer: Lipidomic and Functional Insights

TL;DR

This study shows that CHPT1 and phosphatidylcholine metabolism play a key role in colorectal cancer drug resistance, and targeting this pathway with edelfosine can restore chemotherapy sensitivity.

Contribution

The study identifies CHPT1-driven lipid metabolism as a novel metabolic vulnerability in colorectal cancer chemoresistance.

Findings

CHPT1 overexpression increases phosphatidylcholine levels and promotes chemoresistance in colorectal cancer cells.

Edelfosine restores chemotherapy sensitivity by targeting the Kennedy pathway in CHPT1-high resistant cells.

High CHPT1 expression correlates with poor patient survival in colorectal cancer.

Abstract

What are the main findings?
CHPT1-driven phosphatidylcholine remodeling acts as a key metabolic determinant of chemoresistance in colorectal cancer.CHPT1 overexpression promotes multidrug resistance and is associated with poor patient survival in colorectal cancer (Human Protein Atlas analysis).Lipidomic profiling identifies altered PC and LPC levels as a metabolic signature of resistant cells.Edelfosine sensitizes CHPT1-high resistant colorectal cancer cells to chemotherapy by targeting the Kennedy pathway.

CHPT1-driven phosphatidylcholine remodeling acts as a key metabolic determinant of chemoresistance in colorectal cancer.

CHPT1 overexpression promotes multidrug resistance and is associated with poor patient survival in colorectal cancer (Human Protein Atlas analysis).

Lipidomic profiling identifies altered PC and LPC levels as a metabolic signature of resistant cells.

Edelfosine sensitizes CHPT1-high resistant colorectal cancer cells to chemotherapy by targeting the Kennedy pathway.

What are the implication of the main findings?
CHPT1-mediated lipid remodeling represents a previously underexplored metabolic vulnerability in colorectal cancer.Targeting the Kennedy pathway may provide a therapeutic strategy to overcome chemoresistance in CHPT1-overexpressing tumors.

CHPT1-mediated lipid remodeling represents a previously underexplored metabolic vulnerability in colorectal cancer.

Targeting the Kennedy pathway may provide a therapeutic strategy to overcome chemoresistance in CHPT1-overexpressing tumors.

Chemoresistance remains a major barrier to effective colorectal cancer (CRC) therapy, yet its metabolic underpinnings are poorly defined. Here, we integrate lipidomic profiling, enzymatic analysis, and functional perturbation approaches to elucidate the contribution of phosphatidylcholine (PC) metabolism and its biosynthetic regulator Choline Phosphotransferase 1 (CHPT1) to drug response. Comparative analysis of chemosensitive and chemoresistant CRC cell lines revealed that resistant HT29 cells exhibited significantly higher PC content and altered PC/lysophosphatidylcholine (LPC)ratios relative to sensitive counterparts. Importantly, functional perturbation confirmed causality: CHPT1 overexpression in SW620 cells was sufficient to promote PC accumulation and confer a chemoresistant phenotype. These findings identify CHPT1 as a metabolic gatekeeper of chemoresistance. Consistently, Human Protein Atlas survival analyses further support its clinical relevance, as elevated CHPT1 expression correlates with poor patient outcomes in CRC. Mechanistically, CHPT1-driven PC enrichment may sustain pro-survival signaling, while reducing lysophospholipid-mediated stress pathways. To therapeutically target this vulnerability, we investigated edelfosine (Edel), an alkyl-lysophospholipid that disrupts lipid rafts and inhibits PC biosynthesis upstream of CHPT1. Notably, edelfosine-mediated disruption of the Kennedy pathway enhances chemosensitivity in the resistant CRC model. Collectively, our study identifies CHPT1 and PC metabolism as central determinants of CRC drug response and proposes edelfosine-based metabolic reprogramming as a promising strategy to overcome resistance.

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