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RhoGDI2 up-regulates P-glycoprotein expression via Rac1 in gastric cancer cells

Zhong Zheng1, Bingya Liu2, Xiaohua Wu1

  • 1Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai, 200032 People's Republic of China.

Cancer Cell International
|April 23, 2015
PubMed

Insights

Rho Guanine nucleotide Dissociation Inhibitor 2 (RhoGDI2) induces multidrug resistance (MDR) in gastric cancer by increasing P-glycoprotein (P-gp) expression. This occurs through the activation of Rac1, highlighting a novel therapeutic target for overcoming MDR.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) presents a significant challenge in gastric cancer treatment.
  • Rho Guanine nucleotide Dissociation Inhibitor 2 (RhoGDI2) was previously identified as a factor in 5-fluorouracil (5-FU) resistance in colon cancer cells.

Purpose of the Study:

  • To investigate the role of RhoGDI2 in inducing MDR in gastric cancer cells.
  • To elucidate the underlying molecular mechanism by which RhoGDI2 confers drug resistance.

Main Methods:

  • Stable transfection of MKN-45 gastric cancer cells with RhoGDI2 or control vector.
  • Quantification of P-glycoprotein (P-gp) mRNA, protein expression, and activity.
  • Immunohistochemical analysis of RhoGDI2 and P-gp expression in gastric cancer tissues.
  • Assessment of Rac1 activity and modulation using siRNA.

Main Results:

  • Ectopic RhoGDI2 expression significantly increased P-gp mRNA (130%), protein (230%), and activity (35%) in MKN-45 cells.
  • RhoGDI2 expression positively correlated with P-gp levels in gastric cancer tissues.
  • RhoGDI2 enhanced Rac1 activity, and silencing Rac1 abolished P-gp expression.

Conclusions:

  • RhoGDI2 induces multidrug resistance in gastric cancer by up-regulating P-gp expression.
  • The RhoGDI2-mediated induction of P-gp occurs through the activation of the Rac1 pathway.
  • Targeting the RhoGDI2/Rac1/P-gp axis may offer a strategy to overcome MDR in gastric cancer.
Keywords:
Gastric cancerMultidrug resistanceP-gpRac1RhoGDI2

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