Oncotarget

Research Papers:

ROS-independent Nrf2 activation in prostate cancer

Ilaria Bellezza _, Paolo Scarpelli, Salvatore V. Pizzo, Silvia Grottelli, Egidia Costanzi and Alba Minelli

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Oncotarget. 2017; 8:67506-67518. https://doi.org/10.18632/oncotarget.18724

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Abstract

Ilaria Bellezza1, Paolo Scarpelli1, Salvatore V. Pizzo2, Silvia Grottelli1, Egidia Costanzi1 and Alba Minelli1

1Department of Experimental Medicine, University of Perugia, Perugia, Italy

2Duke University School of Medicine, Durham, NC, USA

Correspondence to:

Ilaria Bellezza, email: ilaria.bellezza@unipg.it

Paolo Scarpelli, email: paolo.scarpelli@unipg.it

Keywords: GRP78/BiP, Nrf2, Akt, Anti-GRP78/BiP antibody, dexamethasone

Received: April 12, 2017     Accepted: May 23, 2017     Published: June 28, 2017

ABSTRACT

In prostate cancer, oxidative stress and the subsequent Nrf2 activation promote the survival of cancer cells and acquired chemoresistance. Nrf2 links prostate cancer to endoplasmic reticulum stress, an event that triggers the unfolded protein response, aiming to restore cellular homeostasis as well as an adaptive survival mechanism. Glucose-regulated protein of 78 kD /immunoglobulin heavy chain binding protein (GRP78/BiP) is a key molecular chaperone in the endoplasmic reticulum that, when expressed at the cell surface, acts as a receptor for several signaling pathways enhancing antiapoptotic and proliferative signals. We showed GRP78/BiP translocation to PC3 cell surface in the presence of tunicamycin, an ER stress inductor, and demonstrated the existence of a GRP78/BiP-dependent non-canonical Nrf2 activation, responsible for increased resistance to ER-stress induced apoptosis. We found that, even in the absence of ROS production, tunicamycin causes Nrf2 activation, and activates Akt signaling, events bulnted by anti-GRP78/BiP antibody treatment. The presence of GRP78/BiP at the cell surface might be exploited for the immunotherapeutic strategy of prostate cancer since its blockage by anti-GRP78/BiP antibodies might promote cancer death by suppressing some of the several molecular protective mechanisms found in aggressive cancer cells.


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