To be or not to be a fat burner, that is the question for cpt1c in cancer cells

Abstract

There is an urgent need to identify reliable genetic biomarkers for accurate diagnosis, prognosis, and treatment of different tumor types. Described as a prognostic marker for many tumors is the neuronal protein carnitine palmitoyltransferase 1 C (CPT1C). Several studies report that CPT1C is involved in cancer cell adaptation to nutrient depletion and hypoxia. However, the molecular role played by CPT1C in cancer cells is controversial. Most published studies assume that, like canonical CPT1 isoforms, CPT1C is a mediator of fatty acid transport to mitochondria for beta-oxidation, despite the fact that CPT1C has inefficient catalytic activity and is located in the endoplasmic reticulum. In this review, we collate existing evidence on CPT1C in neurons, showing that CPT1C is a sensor of nutrients that interacts with and regulates other proteins involved in lipid metabolism and transport, lysosome motility, and the secretory pathway. We argue, therefore, that CPT1C expression in cancer cells is not a direct regulator of fat burn, but rather is a regulator of lipid metabolic reprograming and cell adaptation to environmental stressors. We also review the clinical relevance of CPT1C as a prognostic indicator and its contribution to tumor growth, cancer invasiveness, and cell senescence. This new and integrated vision of CPT1C function can help better understand the metabolic plasticity of cancer cells and improve the design of therapeutic strategies.

CPT1C-positive cancer-associated fibroblast facilitates immunosuppression through promoting IL-6-induced M2-like phenotype of macrophage

“…CPT1C has been shown to exacerbate the severity of GC previously. 5–7 To characterize the role of CPT1C in the tumor microenvironment (TME), we analyzed the scRNA-seq data encompassing 118,027 cells from 40 samples of 29 GC patients and divided them into 9 distinct categories based on their transcriptional features ( Figure 1(a) ). Next, we assessed the expression of CPT1C across these cell types and observed that some subpopulations of fibroblasts exhibited a remarkably high expression of CPT1C, followed by endothelial and smooth muscle cells ( Figure 1(b,c) ).…”

“… 4 CPT1C, an atypical isoform with limited catalytic activity, stands out due to its role as a nutrient sensor regulating cancer cell metabolic reprogramming in response to the dynamic TME. 5 In GC, studies have highlighted the association of elevated CPT1C expression with unfavorable prognosis, enhanced cancer cell proliferation, and distant metastasis. 6 , 7 However, whether CPT1C correlates with any key components in TME and its potential implication in immunomodulation are largely unknown in GC.…”

APC/C-regulated CPT1C promotes tumor progression by upregulating the energy supply and accelerating the G1/S transition

“…Several findings have shown that CPT1C is localized in the endoplasmic reticulum of stem cells and neurons but not in the mitochondria [ 55 , 56 ]. CPT1C has also been detected in mitochondria-associated membranes and microsomes in MCF7 cells [ 57 ]. Our data indicated that CPT1C was present in mitochondria in HeLa cells.…”

Acyl-Carnitines Exert Positive Effects on Mitochondrial Activity under Oxidative Stress in Mouse Oocytes: A Potential Mechanism Underlying Carnitine Efficacy on PCOS

“…In cancer cells, CPT1C expression is known to regulate lipid metabolic reprograming and cell adaptation to environmental stressors. In neurons, it regulates metabolism and function by interacting with proteins involved in the regulation of lipid metabolism, Golgi-mediated secretory transport, and the endolysosomal system [ 75 ].…”