TY - JOUR
T1 - ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer
AU - Grandi, Alberto
AU - Santi, Alice
AU - Campagnoli, Susanna
AU - Parri, Matteo
AU - De Camilli, Elisa
AU - Song, Chaojun
AU - Jin, Boquan
AU - Lacombe, Aurelien
AU - Castori-Eppenberger, Serenella
AU - Sarmientos, Paolo
AU - Grandi, Guido
AU - Viale, Giuseppe
AU - Terracciano, Luigi
AU - Chiarugi, Paola
AU - Pileri, Piero
AU - Grifantini, Renata
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - ERMP1
KW - Immunohistochemistry
KW - Monoclonal antibody
KW - Oxidative stress
KW - UPR
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UR - http://www.scopus.com/inward/citedby.url?scp=84993999917&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11550
DO - 10.18632/oncotarget.11550
M3 - Article
AN - SCOPUS:84993999917
VL - 7
SP - 63596
EP - 63610
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 39
ER -