36eaf85eec41078d8336cd9cf7faf094 pmc_9864098.pdf f5818a8451c64d542d930e7a7dff8979fe98033e pmc_9864098.pdf 2e132bced3ed40541067e7845acdb026f86a640769cdfe5b2a05daff95a1e89a pmc_9864098.pdf Title: Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer Subject: 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. Keywords: CPT1C; chemoresistance; drug uptake; breast cancer; doxorubicin; plasma membrane; lipid remodelling; fatty acid saturation Author: Helena Muley, Karmele Valencia, Josefina Casas, Bea Moreno, Luis Botella, Fernando Lecanda, Rut Fadó and Núria Casals Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sat Jan 14 11:18:40 2023 CET ModDate: Sat Jan 14 11:24:52 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4325014 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WYFLDJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 ARIQJE+VnURWPalladioL Type 1 Custom yes yes no 15 0 CDPUBF+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 DGNCUG+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 FQMBXF+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 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edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: CPT1C Silencing Impairs DOX Uptake in MDA-MB-231 Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: CPT1C Silencing Promotes Resistance to DOX in BC Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: CPT1C Silencing Impairs Liposomal-DOX Uptake and Sensitivity in MDA-MB-231 Cells Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: CPT1C as a Predictive Biomarker of Anthracycline Response Is of Prognostic Value for Patients with the TNBC and HER2+ BC Subtypes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Cell Culture Destination: 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References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Info: Title: Cpt1c Downregulation Causes Plasma Membrane Remodelling and Anthracycline Resistance in Breast Cancer Author: Helena Muley, Karmele Valencia, Josefina Casas, Bea Moreno, Luis Botella, Fernando Lecanda, Rut Fadó and Núria Casals Subject: 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. Keywords: CPT1C; chemoresistance; drug uptake; breast cancer; doxorubicin; plasma membrane; lipid remodelling; fatty acid saturation Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sat Jan 14 11:18:40 CET 2023 ModDate: Sat Jan 14 11:24:52 CET 2023 ID: 0x7eea96f768390be01a44b46686e260df, 0x7eea96f768390be01a44b46686e260df Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: CDPUBF+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 121 FontDescriptor: FontName: CDPUBF+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ALMJEC+EURM10 FontSubset: true FirstChar: 11 LastChar: 33 FontDescriptor: FontName: ALMJEC+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: MPUDFL+PazoMath FontSubset: true FirstChar: 68 LastChar: 68 FontDescriptor: FontName: MPUDFL+PazoMath Flags: Symbolic FontBBox: -40, -283, 878, 946 FontFile: true Font: 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