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Tumor Biology

, Volume 37, Issue 9, pp 12153–12160 | Cite as

SH3GL1 inhibition reverses multidrug resistance in colorectal cancer cells by downregulation of MDR1/P-glycoprotein via EGFR/ERK/AP-1 pathway

  • Haitao Guan
  • Ping Zhao
  • Zhijun Dai
  • Xiaoxu Liu
  • Xijing Wang
Original Article

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.

Keywords

Colorectal cancer Multidrug resistance SH3GL1 MDR1 P-glycoprotein 

Notes

Compliance with ethical standards

The study was performed with the approval of the Ethics Committee of the Second Affiliated Hospital of Xi’an Jiaotong University. Written informed consents were obtained from each patient before study initiation.

Conflicts of interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Haitao Guan
    • 1
  • Ping Zhao
    • 2
  • Zhijun Dai
    • 1
  • Xiaoxu Liu
    • 1
  • Xijing Wang
    • 1
  1. 1.Department of OncologyThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  2. 2.Department of GastroenterologyThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina

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