title: Niemann-Pick disease type C1(NPC1) is involved in resistance against imatinib in the imatinib-resistant Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI.
abstract: Niemann-Pick disease type C1 (NPC1) is involved in cholesterol trafficking and may normally function as a transmembrane efflux pump. Previous studies showed that its dysfunction can lead to cholesterol and daunorubicin accumulation in the cytoplasmic endosomal/lysosomal system, lead to Niemann-Pick disease and resistance to anticancer drugs. In the present study, NPC1 was shown by microarray analysis to be more highly expressed in the Ph+ acute lymphoblastic leukemia cell line SUP-B15/RI, an imatinib-resistant variant of SUP-B15/S cells without bcr-abl gene mutation established in our lab. Further investigation revealed a defect in the functional capacity of the NPC1 protein demonstrated by filipin staining accompanied by a lower intracellular imatinib mesylate(IM) concentration by high-performance liquid chromatography in SUP-B15/RI compared with SUP-B15/S cells. Furthermore, U18666A, an inhibitor of NPC1 function, was used to block cholesterol trafficking to imitate the NPC1 defect in SUP-B15/S cells, leading to higher NPC1 expression, stronger filipin fluorescence, lower intracellular IM concentrations and greater resistance against IM. Samples from non-mutated relapsed Ph+ ALL patients also showed higher NPC1 expression compared with IM-sensitive patients. Our experiment may reveal a new mechanism of IM resistance in Ph+ ALL.
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China.
authors.forename: Duolan
authors.initials: D
authors.lastname: Naren
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China. Electronic address: gongyuping2010@aliyun.com.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China.
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yan
authors.affiliation: Joint Laboratory of Reproductive Medicine, SCU-CUHK, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China; Department of Obstetric and Gynecologic Diseases, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Joint Laboratory of Reproductive Medicine, SCU-CUHK, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China; Department of Obstetric and Gynecologic Diseases, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, 610041, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D000068877:Imatinib Mesylate
keywords: Cholesterol regulation; Drug resistance; Drug transport; Leukemia; Lysosome; Niemann-Pick disease type C1