Activation of type 4 metabotropic glutamate receptor promotes cell apoptosis and inhibits proliferation in bladder cancer

Bladder cancer, the second most common genitourinary malignancy, severely endangers the human health. Rising evidence suggests that metabotropic glutamate receptors (mGluRs) are involve in tumor progression. In this study, we observed that metabotropic glutamate receptor 4 (mGluR4) was functionally expressed in normal and cancerous bladder cells and its expression was positively correlated with high bladder cancer grading. We further confirmed that the activation of mGluR4 by VU0155041, an mGluR4-specific agonist, decreased cyclic adenosine monophosphate (cAMP) concentration and cell viability, promoted apoptosis and inhibited proliferation in bladder cancer cells, whereas MSOP (group III mGluR antagonist) or mGluR4 knockdown eliminated the effects of mGluR4 activity. Western blotting revealed the decreased cyclin D1 expression, increased procaspase-8/9/3 cleavage, and unbalanced Bcl-2/Bax expression in bladder cancer cell lines after mGluR4 activation, and likewise MSOP and mGluR4 knockdown abrogated the actions of mGluR4 activity. In vivo study showed that mGluR4 activation significantly inhibited tumor growth of bladder cancer via suppressing proliferation and promoting apoptosis. Furthermore, upregulation of phosphatase and tensin homolog (PTEN) and inhibition of Akt phosphorylation were also observed after mGluR4 activation. Similar with VU0155041, the Akt-specific inhibitor markedly promoted apoptosis and inhibited proliferation. Nevertheless, the PTEN-specific inhibitor significantly abolished the mGluR4 activation-induced cell apoptosis and proliferative inhibition in bladder cancer cell lines. These results indicate that mGluR4 can regulate the switch between survival and death via the cAMP/PTEN/AKT signaling pathway in bladder cancer cells. Our findings suggest that mGluR4 has diagnostic and prognostic potential for bladder cancer, and the development of mGluR4 agonist may be a promising strategy for bladder cancer treatment.