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LRIG1, human EGFR inhibitor, reverses multidrug resistance through modulation of ABCB1 and ABCG2

Baohui Liu1, Zhentao Guo1, Huimin Dong1

  • 1Renmin Hospital, Wuhan University, 238 Jiefang Street, Wuhan, Hubei 430060, China.

Brain Research
|March 25, 2015
PubMed

Insights

Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) reverses multidrug resistance (MDR) in glioblastoma by inhibiting the epidermal growth factor receptor (EGFR). This downregulation of EGFR subsequently reduces ATP-binding cassette, sub-family B member 1 (ABCB1) and ABCG2 expression, overcoming MDR.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is known to improve chemosensitivity in U251 cells.
  • The role of LRIG1 in multidrug resistance (MDR) of glioblastoma remains largely uncharacterized.
  • Glioblastoma exhibits significant resistance to chemotherapy, necessitating novel therapeutic targets.

Purpose of the Study:

  • To investigate the role of LRIG1 in reversing multidrug resistance (MDR) in glioblastoma.
  • To elucidate the molecular mechanisms underlying LRIG1-mediated MDR reversal.
  • To explore the relationship between LRIG1, epidermal growth factor receptor (EGFR), and drug resistance markers ABCB1 and ABCG2.

Main Methods:

  • Comparative analysis of LRIG1 expression in glioblastoma tissues with different O6-methylguanine DNA methyltransferase (MGMT) promoter methylation statuses.
  • Assessment of LRIG1 expression in multidrug-resistant U251/TMZ cells versus parental U251 cells.
  • Overexpression of LRIG1 in U251 cells and evaluation of its impact on MDR phenotypes.
  • Measurement of ATP-binding cassette, sub-family B member 1 (ABCB1) and ABCG2 expression following LRIG1 overexpression.
  • Investigating the role of EGFR in mediating LRIG1's effects on MDR, ABCB1, and ABCG2 using EGFR knockdown experiments.

Main Results:

  • LRIG1 expression was significantly higher in MGMT promoter methylation-positive glioblastoma tissues.
  • LRIG1 expression was markedly decreased in multidrug-resistant U251/TMZ cells compared to U251 cells.
  • Overexpression of LRIG1 reversed MDR in U251 cells and suppressed the expression of ABCB1 and ABCG2.
  • LRIG1 downregulated ABCB1 and ABCG2 by inhibiting EGFR expression.
  • EGFR knockdown partially abrogated the MDR-reversing effects of LRIG1.

Conclusions:

  • LRIG1 plays a crucial role in reversing multidrug resistance (MDR) in glioblastoma.
  • LRIG1 exerts its MDR-reversing effects by negatively regulating EGFR signaling.
  • The LRIG1-EGFR axis suppresses the expression of ABCB1 and ABCG2, offering a novel therapeutic strategy for overcoming glioblastoma MDR.
Keywords:
ATP-binding cassetteEpidermal 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)

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