Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer.
Helena MuleyKarmele ValenciaJosefina CasasBea MorenoLuis BotellaFernando LecandaRut FadóNúria CasalsPublished in: International journal of molecular sciences (2023)
Breast cancer (BC) is the most common malignancy in women worldwide. While the main systemic treatment option is anthracycline-containing chemotherapy, chemoresistance continues to be an obstacle to patient survival. Carnitine palmitoyltransferase 1C (CPT1C) has been described as a poor-prognosis marker for several tumour types, as it favours tumour growth and hinders cells from entering senescence. At the molecular level, CPT1C has been associated with lipid metabolism regulation and important lipidome changes. Since plasma membrane (PM) rigidity has been associated with reduced drug uptake, we explored whether CPT1C expression could be involved in PM remodelling and drug chemoresistance. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) lipid analysis of PM-enriched fractions of MDA-MB-231 BC cells showed that CPT1C silencing increased PM phospholipid saturation, suggesting a rise in PM rigidity. Moreover, CPT1C silencing increased cell survival against doxorubicin (DOX) treatment in different BC cells due to reduced drug uptake. These findings, further complemented by ROC plotter analysis correlating lower CPT1C expression with a lower pathological complete response to anthracyclines in patients with more aggressive types of BC, suggest CPT1C as a novel predictive biomarker for BC chemotherapy.
Keyphrases
- poor prognosis
- high resolution mass spectrometry
- particulate matter
- liquid chromatography
- air pollution
- long non coding rna
- polycyclic aromatic hydrocarbons
- heavy metals
- induced apoptosis
- mass spectrometry
- cell cycle arrest
- water soluble
- signaling pathway
- fatty acid
- drug induced
- oxidative stress
- cell death
- risk assessment
- drug delivery
- squamous cell carcinoma
- cell proliferation
- metabolic syndrome
- polycystic ovary syndrome
- high resolution
- emergency department
- replacement therapy
- smoking cessation
- childhood cancer
- early breast cancer