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CPT1A upregulation promotes colon cancer

A paper published in Cell Death and Disease, has identified that CPT1A upregulation is important for the tumour promoting effects of adipocytes in colon cancer.

A transfer

Altered metabolism is one of Hanahan and Weinberg’s Hallmarks of Cancer. Emerging evidence suggests that the tumour microenvironment (TME) is critical in shaping the landscape of cancer metabolism. Adipocytes within the TME constitute a major cell type. When metastatic colon cancer cells first disseminate, they often encounter adipocytes. Previous work has shown that cancer-associated adipocytes promote tumour growth and progression. Researchers have identified that adipocytes secrete growth factors and proinflammatory cytokines into the TME. However, the direct interaction that adipocytes have on tumorigenic properties of cancer cells is largely unknown.

In ovarian cancer models, reports have shown that lipids produced in adipocytes can be transferred to cancer cells to promote tumour growth. In addition, researchers have identified that the uptake of fatty acids from adipocytes allows colon cancer cells to survive in nutrient deprived environments by upregulating mitochondrial fatty acid oxidation (FAO). Researchers have also seen this transfer in breast and melanoma cancer models. Importantly, the presence of cancer cells encourages the release of fatty acids from adipocytes by promoting lipolysis. This suggests that there is a two-way communication between cancer cells and adipocytes in the TME.

CPT1A-mediated tumour effects

The molecular mechanism underpinning this lipid transfer is unclear. In this study, researchers further characterised the role of CPT1A in mediating tumour promotion of adipocytes in colon cancer. CPT1A is a rate-limiting enzyme required for mitochondrial FAO. The team used primary colon cancer cells, 3D tumour organoids and in vivo xenograft models to show that uptake of fatty acids promotes the expression of CPT1A through activation of PPARδ.

The team observed that the presence of adipocytes or fatty acids stimulated expression of CPT1A by activating PPARδ- dependent transcription. PPARδ is a lipid sensing nuclear receptor that long-chain fatty acids activate in order to regulate cellular metabolism. They found that knockdown of CPT1A attenuated fatty acid utilisation and eliminated the pro-survival advantage provided by adipocytes. This was due to the decreased fatty acid degradation via FAO. Moreover, they found that in 3D tumour organoid models, CPT1A downregulation induced differentiation and attenuated the effects of fatty acids on promoting expression of cancer stem cell-associated genes. The team also found that CPT1A was key for adipocytes to promote tumour growth and inhibition in vivo. Importantly, they identified that β-catenin acetylation is a novel mechanism that connects upregulation of FAO with increased Wnt/β-catenin signalling.

These results demonstrate that CPT1A-dependent FAO is an essential metabolic pathway that connects adipocyte-mediated regulation of cellular metabolism to Wnt signalling in colon cancer cells. As adipocytes preferentially upregulate CPT1A, these findings indicate that CPT1A inhibition could be an effective method for blocking the tumour promoting effects of adipocytes in colon cancer.

Image credit: By Mohammed Haneefa Nizamudeen –

More on these topics

Cancer / Cancer Research / Colon Cancer / Tumour