title: LRIG1, human EGFR inhibitor, reverses multidrug resistance through modulation of ABCB1 and ABCG2.
abstract: In our previous study, we have found that leucine-rich repeats and immunoglobulin-like domains 1(LRIG1) can improve the chemosensitivity in U251 cells whereas the role of LRIG1 in multidrug resistance (MDR) remains unknown. Here, we reported that LRIG1 can reverse MDR by inhibiting epidermal growth factor (EGF) receptor (EGFR) and secondary inhibiting ATP-binding cassette, sub-family B member 1(ABCB1) and ATP-binding cassette, sub-family G (WHITE), member 2 (ABCG2). Our data showed that the expression of LRIG1 was significantly higher in O6-methylguanine DNA methyltransferase (MGMT) Promoter Methylation positive glioblastoma tissues compared to MGMT Promoter Methylation negative glioblastoma tissues. In addition, we found that LRIG1 expression was significantly decreased in MDR cells U251/TMZ compared to U251cells. Our results demonstrated that over-expression of LRIG1 can reverse the MDR. The expression of ABCB1 and ABCG2 were markedly suppressed when LRIG1 was over-expressed, supporting the negative relationship between LRIG1 level and ABCB1 and ABCG2 level in human specimen. Furthermore, we found that LRIG1 downregulated ABCB1 and ABCG2 through suppressing EGFR expression. In case of EGFR knockdown, the effect of LRIG1 on regulating MDR, ABCB1 and ABCG2 was partially compromised. Our results, for the first time, showed that LRIG1 can reverse MDR in glioblastoma, by negatively regulating EGFR and secondary suppressing the levels of ABCB1 and ABCG2.
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Baohui
authors: B
authors: Liu
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Zhentao
authors: Z
authors: Guo
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Huimin
authors: H
authors: Dong
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Tian
authors: T
authors: Daofeng
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Qiang
authors: Q
authors: Cai
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Baowei
authors: B
authors: Ji
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Shenqi
authors: S
authors: Zhang
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Liquan
authors: L
authors: Wu
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Junmin
authors: J
authors: Wang
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Long
authors: L
authors: Wang
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.
authors: Xiaonan
authors: X
authors: Zhu
authors: Shiyan Taihe Hospital, Hubei University of Medicine, 32 South Renmin Street, Shiyan, Hubei 442000, China.
authors: Yue
authors: Y
authors: Liu
authors: Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China. Electronic address: chenqx666@sohu.com.
authors: Qianxue
authors: Q
authors: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008745:Methylation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: ATP-binding cassette; Epidermal growth factor receptor (EGFR); Leucine-rich repeats and immunoglobulin-like domains 1(LRIG1); Member 2 (ABCG2); Multidrug resistance (MDR); Sub-family B member 1(ABCB1); Sub-family G (WHITE)