title: SH3GL1 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via EGFR/ERK/AP-1 pathway.
abstract: Multidrug resistance is one of the major reasons colorectal cancer (CRC) chemotherapy-based treatments fail, and novel biologically based therapies are urgently needed. Src homology 3 (SH3)-domain GRB2-like protein 1 (SH3GL1) is a membrane-bound protein which was found to be involved in tumor formation, progression, and metastasis. In this study, immunohistochemistry staining, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis revealed a high expression of SH3GL1 in human CRC tumor specimens and several CRC cells resistant to chemotherapeutics. Cell Counting Kit-8 (CCK-8) assay showed that transfection of pCDNA3.1(+)-SH3GL1 increased while transfection of SH3GL1 siRNA decreased cell viability in response to 5-fluorouracil (5-FU) treatment (P < 0.05). Further studies indicated that transfection of SH3GL1 siRNA significantly downregulated multidrug resistance protein 1 (MDR1)/P-glycoprotein expression (P < 0.05), decreased MDR1 promoter activity and activator protein-1 (AP-1) binding activity (P < 0.05), and inhibited the activation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling (P < 0.05) in CRC cells resistant to chemotherapeutics. Transfection of pCDNA3.1(+)-SH3GL1 caused the opposite effect. Additionally, pre-treatment with either EGFR kinase inhibitor PD153035 or ERK1/2 kinase inhibitor PD98059 in HCT116/5-FU cells partly inhibits P-glycoprotein expression and AP-1 binding activity (P < 0.05). In conclusion, we confirmed that inhibition of SH3GL1 reverses multidrug resistance through declining P-glycoprotein expression via the EGFR/ERK/AP-1 pathway.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West NO. 5 Road, Xi'an, Shaanxi Province, 710004, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West NO.5 Road, Xi'an, Shaanxi Province, 710004, China. pingzhaogas@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West NO. 5 Road, Xi'an, Shaanxi Province, 710004, China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West NO. 5 Road, Xi'an, Shaanxi Province, 710004, China.
authors.forename: Xiaoxu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 West NO. 5 Road, Xi'an, Shaanxi Province, 710004, China.
authors.forename: Xijing
authors.initials: X
authors.lastname: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology; D000368:Aged; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D047908:Intracellular Signaling Peptides and Proteins; C105159:SH3GL1 protein, human; D018808:Transcription Factor AP-1; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Colorectal cancer; MDR1; Multidrug resistance; P-glycoprotein; SH3GL1