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G(alpha)12/13 inhibition enhances the anticancer effect of bortezomib through PSMB5 downregulation

Yoon Mee Yang1, Sanghwan Lee, Chang Won Nam

  • 1Department of Pharmacy, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.

Carcinogenesis
|May 19, 2010
PubMed

Insights

G protein alpha 12/13 (Gα12/13) expression influences cancer cell sensitivity to bortezomib, a proteasome inhibitor. Inhibiting Gα12/13 enhances bortezomib

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Bortezomib is a proteasome inhibitor used in cancer therapy, but its efficacy varies due to differential proteasome subunit expression.
  • G protein alpha 12/13 (Gα12/13) are signal transducers involved in various cellular pathways, with potential roles in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate if cancer cells exhibit differential sensitivity to bortezomib based on Gα12/13 expression.
  • To determine if Gα12/13 influences proteasome subunit expression and activity, thereby affecting bortezomib efficacy.

Main Methods:

  • Differential sensitivity assays of cancer cell lines (Huh7, SNU886, SK-Hep1, SNU449, MiaPaCa2) to bortezomib.
  • Overexpression of constitutively active Gα12/13 mutants (Gα12QL, Gα13QL) and disruption of G protein-coupled receptor-G protein coupling (CT12, CT13) via minigene transfection.
  • Real-time PCR, immunoblotting, and proteasome activity assays to assess proteasome subunit expression (PSMB5, MCPH1, PSMA1) and activity.

Main Results:

  • Mesenchymal-type cancer cells with higher Gα12/13 levels showed greater resistance to bortezomib compared to epithelial-type cells.
  • Overexpression of Gα12QL or Gα13QL reduced bortezomib-induced cytotoxicity, while CT12/CT13 transfection increased sensitivity.
  • Gα12/13 inhibition enhanced bortezomib's ability to repress PSMB5 expression and proteasome activity, indicating a mechanism for overcoming resistance.

Conclusions:

  • Gα12/13 antagonizes the anticancer effects of bortezomib, likely by modulating proteasome subunit expression and activity.
  • Inhibition of Gα12/13 may represent a therapeutic strategy to enhance bortezomib efficacy in cancer treatment.
  • This study provides insights into the Gα12/13 pathway's role in regulating proteasomal activity and bortezomib response.

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