Downregulation of arginyltransferase (Ate1) enhances bortezomib-induced cell death in human glioma cells.

BONNET, LAURA V.; JÉSICA FLORES MARTÍN; PALANDRI ANABELA; HALLAK, MARTA E.; GALIANO, MAURICIO R.

Cordoba

Congreso; XXXIII Reunión Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

Sociedad Argentina de Investigación en Neurociencias

The enzyme Ate1 mediates the post-translational addition of an Arg to proteins bearing acidic N-terminal amino acids that are mainly target to proteasomal degradation or macroautophagy. Previous studies reported that Ate1 downregulation suppresses cell death induced by different stressors. In addition, Ate1-knockout fibroblasts exhibit tumorigenic properties, including exacerbated contact-independent growth and chromosomal aberrations. We recently reported that increased cell membrane exposure of an Ate1 substrate (arginylated calreticulin) modulates the sensitivity to proteasomal inhibitor bortezomib (BT) of human oligodendroglioma (HOG) cells. Hence, further assessment is required to determine the Ate1 implication in the tumorigenic progression of BT treated cells. HOG cell death induced by BT comes through a mechanism that involves activation of the unfolded protein response (UPR) mediators, including the transcriptional activation of the spliced mRNA xbp1 and concomitant upregulation of DR5-R membrane expression. Moreover, we do not observed changes in autophagy flux at different time and drug doses. Strikingly, we found that Ate1 knockdown in HOG increases their sensitivity to BT in a macroautophagy independent way, suggesting that apoptosis of glioma cells induced by BT is strongly influenced by Ate1 expression. We postulates that Ate1 is an essential enzyme that regulates stress response and cell fate controlling the tumorigenic progress of cancer cells.