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Proteomics Analysis of 5-Fluorouracil- and Gemcitabine-Resistant Cholangiocarcinoma Cell Lines: Identification of Potential Therapeutic Targets and Prognostic Markers

ABSTRACT: Cholangiocarcinoma (CCA) poses a significant health challenge, especially in Asian countries. Late-stage diagnoses limit the availability of curative surgical options, underscoring the crucial role of chemotherapy. However, drug resistance presents a formidable obstacle, resulting in recurrent tumors. Despite the revolutionary impact of proteomics on cancer research, the exploration of drug-resistant mechanisms in CCA remains unexplored. In this study, we established 5-fluorouracil (5-FU)- and gemcitabine-resistant CCA cell lines, KKU-213FR and KKU-213GR, derived from the KKU-213A parental line. These cell lines exhibited robust drug resistance, heightened migration, and invasion capabilities.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Sumalee Obchoei

PROVIDER: PXD049309 | JPOST Repository | Wed Jul 03 00:00:00 BST 2024

REPOSITORIES: jPOST

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Project description:In pancreatic cancer the survival rate is low, as the available treatment options usually only extend survival and seldom produce a cure. Drug resistance and disease reoccurrence is the typical reason for death after cancer diagnosis. 5-Fluorouracil (5-FU) is the main chemostatic used in first line therapy. However the majority of the tumors become resistant to treatment. To investigate acquired 5-FU resistance in pancreatic adenocarcinoma, we established chemoresistant monoclonal cell lines from the Panc03.27 cell line by long-term exposure to 5-FU. In addition to increased expression of markers associated with multidrug resistance, the 5-FU resistant clones showed alterations typical of the process of epithelial-to-mesenchymal transition (EMT), including upregulation of mesenchymal markers and increased invasiveness. Microarray analysis revealed the L1CAM pathway as one of the most upregulated pathways in the chemoresistant clones, which was confirmed on RNA and protein levels. Expression of the adhesion molecule L1CAM is associated with a chemoresistant and migratory phenotype of pancreatic cancer. Using esiRNA targeting L1CAM, or by blocking the extracellular part of L1CAM with monoclonal antibodies, we discovered that the increased invasiveness observed in the chemoresistant cells depends on L1CAM. Using esiRNA targeting β-catenin and/or Slug, we discovered that L1CAM expression depends on Slug rather than β-catenin in the 5-FU resistant cells. We demonstrate a functional link between Slug and the expression level of L1CAM in pancreatic cancer cells having undergone EMT following long-term exposure to 5-FU. Our findings provide further insight into the molecular mechanisms leading to a chemoresistant and migratory phenotype in pancreatic cancer cells and indicate the importance of Slug-induced L1CAM in refractory pancreatic cancer. Examination of expression of 5-Fluorouracil (5-FU) Panc03.27 cell line resistant clone versus expression of 5-FU sensitive clones (NT) in 4 replicates per cell lines

			Action	DRS
	KKU-213FR-1_1.mzXML	Mzxml
	KKU-213FR-1_2.mzXML	Mzxml
	KKU-213FR-1_3.mzXML	Mzxml
	KKU-213FR-2_1.mzXML	Mzxml
	KKU-213FR-2_2.mzXML	Mzxml