ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer

Alberto Grandi, Alice Santi, Susanna Campagnoli, Matteo Parri, Elisa De Camilli, Chaojun Song, Boquan Jin, Aurelien Lacombe, Serenella Castori-Eppenberger, Paolo Sarmientos, Guido Grandi, Giuseppe Viale, Luigi Terracciano, Paola Chiarugi, Piero Pileri, Renata Grifantini

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)63596-63610
Number of pages15
JournalOncotarget
Volume7
Issue number39
DOIs
Publication statusPublished - 2016

Keywords

  • ERMP1
  • Immunohistochemistry
  • Monoclonal antibody
  • Oxidative stress
  • UPR

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Grandi, A., Santi, A., Campagnoli, S., Parri, M., De Camilli, E., Song, C., Jin, B., Lacombe, A., Castori-Eppenberger, S., Sarmientos, P., Grandi, G., Viale, G., Terracciano, L., Chiarugi, P., Pileri, P., & Grifantini, R. (2016). ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer. Oncotarget, 7(39), 63596-63610. https://doi.org/10.18632/oncotarget.11550