Reduced expression of annexin A1 promotes gemcitabine and 5-fluorouracil drug resistance of human pancreatic cancer

• Published in: Investigational new drugs 2020-04, Vol.38 (2), p.350-359
• Main Authors: Liu, Qing-Hua, Yong, Hong-Mei, Zhuang, Qing-Xin, Zhang, Xu-Ping, Hou, Ping-Fu, Chen, Yan-Su, Zhu, Ming-Hua, Bai, Jin
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adenocarcinoma; Animals; Annexin A1 - genetics; Annexin A1 - metabolism; Antimetabolites, Antineoplastic - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; c-Jun protein; Cell Line, Tumor; Chemoresistance; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Down-Regulation; Drug development; Drug resistance; Drug Resistance, Neoplasm; Electrophoresis; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gemcitabine; Glycoproteins; Humans; JNK protein; Kinases; Liquid chromatography; Male; MAP Kinase Kinase 4 - metabolism; Mass spectrometry; Mass spectroscopy; Medicine; Medicine & Public Health; Mice, Inbred BALB C; Mice, Nude; Oncology; P-Glycoprotein; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pharmacology/Toxicology; Preclinical Studies; Protein kinase C; Protein Kinase C - metabolism; Proteins; Scientific imaging; Signal Transduction; Spectroscopy; Transcription factors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-019-00785-5

Summary Intrinsic chemoresistance is the main reason for the failure of human pancreatic ductal adenocarcinoma (PDAC) therapy. To identify the candidate protein, we compared the protein expression profiling of PDAC cells and its distinct surviving cells following primary treatment with gemcitabine (GEM) and 5-fluorouracil (5-FU) by two-dimensional electrophoresis combined with liquid chromatography–mass spectrometry or mass spectrometry. A total of 20 differentially expressed proteins were identified, and annexin A1 (ANXA1) was analyzed for further validation. The functional validation showed that the downregulation of ANXA1 contributes to GEM and 5-FU resistance in PDAC cells through protein kinase C/c-Jun N-terminal kinase/P-glycoprotein signaling pathway. Our findings provide a platform for the further elucidation of the underlying mechanisms of PDAC intrinsic chemoresistance and demonstrated that ANXA1 may be a valid marker for anticancer drug development.