Journal Article

Gα<sub>12/13</sub> inhibition enhances the anticancer effect of bortezomib through PSMB5 downregulation

Yoon Mee Yang, Sanghwan Lee, Chang Won Nam, Ji Hee Ha, Muralidharan Jayaraman, Danny N. Dhanasekaran, Chang Ho Lee, Mi-Kyoung Kwak and Sang Geon Kim

in Carcinogenesis

Volume 31, issue 7, pages 1230-1237
Published in print July 2010 | ISSN: 0143-3334
Published online May 2010 | e-ISSN: 1460-2180 | DOI:
Gα12/13 inhibition enhances the anticancer effect of bortezomib through PSMB5 downregulation

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Bortezomib is a proteasome inhibitor approved for anticancer therapy. However, variable sensitivity of tumor cells exists in this therapy probably due to differences in the expression of proteasome subunits. Gα12/13 serves modulators or signal transducers in diverse pathways. This study investigated whether cancer cells display differential sensitivity to bortezomib with reference to Gα12/13 expression, and if so, whether Gα12/13 affects the expression of proteasome subunits and their activities. Bortezomib treatment exhibited greater sensitivities in Huh7 and SNU886 cells (epithelial type) than SK-Hep1 and SNU449 cells (mesenchymal type) that exhibited higher levels of Gα12/13. Overexpression of an active mutant of Gα12 (Gα12QL) or Gα13 (Gα13QL) diminished the ability of bortezomib to induce cytotoxicity in Huh7 cells. Moreover, transfection with the minigene that disturbs G protein-coupled receptor-G protein coupling (CT12 or CT13) increased it in SK-Hep1 cells. Consistently, MiaPaCa2 cells transfected with CT12 or CT13 exhibited a greater sensitivity to bortezomib. Evidence of Gα12/13’s antagonism on the anticancer effect of bortezomib was verified in the reversal by Gα12QL or Gα13QL of the minigenes’ enhancement of cytotoxity. Real-time polymerase chain reaction assay enabled us to identify PSMB5, multicatalytic endopeptidase complex-like-1, and proteasome activator subunit-1 repression by CT12 or CT13. Furthermore, Gα12/13 inhibition enhanced the ability of bortezomib to repress PSMB5, as shown by immunoblotting and proteasome activity assay. Moreover, this inhibitory effect on PSMB5 was attenuated by Gα12QL or Gα13QL. In conclusion, the inhibition of Gα12/13 activities may enhance the anticancer effect of bortezomib through PSMB5 repression, providing insight into the Gα12/13 pathway for the regulation of proteasomal activity.

Journal Article.  5869 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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