ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer
Metrics: PDF 2184 views | HTML 2530 views | ?
Alberto Grandi1, Alice Santi2, Susanna Campagnoli1, Matteo Parri1, Elisa De Camilli3, Chaojun Song4, Boquan Jin4, Aurelien Lacombe5, Serenella Castori-Eppenberger5, Paolo Sarmientos1, Guido Grandi1,6, Giuseppe Viale3,7, Luigi Terracciano5, Paola Chiarugi2, Piero Pileri1, Renata Grifantini1,8
1Externautics SpA, Siena, Italy
2Department of Experimental and Clinical Biomedical Science, University of Florence, Florence, Italy
3Department of Pathology, European Institute of Oncology, Milan, Italy
4Department of Immunology, The Fourth Military Medical University, Xi’an, China
5Institute of Pathology, University Hospital Basel, Basel, Switzerland
6Centre for Integrative Biology - CIBIO, University of Trento, Trento, Italy
7Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
8INGM Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
Renata Grifantini, email: [email protected]
Piero Pileri, email: [email protected]
Keywords: ERMP1, immunohistochemistry, monoclonal antibody, UPR, oxidative stress
Received: May 04, 2016 Accepted: August 11, 2016 Published: August 23, 2016
Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are highly activated in cancer and involved in tumorigenesis and resistance to anti-cancer therapy. UPR is becoming a promising target of anti-cancer therapies. Thus, the identification of UPR components that are highly expressed in cancer could offer new therapeutic opportunity.
In this study, we demonstrate that Endoplasmic Reticulum Metallo Protease 1 (ERMP1) is broadly expressed in a high percentage of breast, colo-rectal, lung, and ovary cancers, regardless of their stage and grade. Moreover, we show that loss of ERMP1 expression significantly hampers proliferation, migration and invasiveness of cancer cells. Furthermore, we show that this protein is an important player in the UPR and defense against oxidative stress. ERMP1 expression is strongly affected by reticular stress induced by thapsigargin and other oxidative stresses. ERMP1 silencing during reticular stress impairs the activation of PERK, a key sensor of the UPR activation. Loss of ERMP1 also prevents the expression of GRP78/BiP, a UPR stress marker involved in the activation of the survival pathway. Finally, ERMP1 silencing in cells exposed to hypoxia leads to inhibition of the Nrf2-mediated anti-oxidant response and to reduction of accumulation of HIF-1, the master transcription factor instructing cells to respond to hypoxic stress. Our results suggest that ERMP1 could act as a molecular starter to the survival response induced by extracellular stresses. Moreover, they provide the rationale for the design of ERMP1-targeting drugs that could act by inhibiting the UPR initial adaptive response of cancer cells and impair cell survival.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.