title: Depletion of the thiol oxidoreductase ERp57 in tumor cells inhibits proliferation and increases sensitivity to ionizing radiation and chemotherapeutics.
abstract: Rapidly growing tumor cells must synthesize proteins at a high rate and therefore depend on an efficient folding and quality control system for nascent secretory proteins in the endoplasmic reticulum (ER). The ER resident thiol oxidoreductase ERp57 plays an important role in disulfide bond formation. Lentiviral, doxycycline-inducible ERp57 knockdown was combined with irradiation and treatment with chemotherapeutic agents. The knockdown of ERp57 significantly enhanced the apoptotic response to anticancer treatment in HCT116 colon cancer cells via a p53-dependent mechanism. Instead of a direct interaction with p53, depletion of ERp57 induced cell death via a selective activation of the PERK branch of the Unfolded Protein Response (UPR). In contrast, apoptosis was reduced in MDA-MB-231 breast cancer cells harboring mutant p53. Nevertheless, we observed a strong reduction of proliferation in response to ERp57 knockdown in both cell lines regardless of the p53 status. Depletion of ERp57 reduced the phosphorylation activity of the mTOR-complex1 (mTORC1) as demonstrated by reduction of p70S6K phosphorylation. Our data demonstrate that ERp57 is a promising target for anticancer therapy due to synergistic p53-dependent induction of apoptosis and p53-independent inhibition of proliferation.
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hussmann
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Janke
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Kranz
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Neumann
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Evgenija
authors.initials: E
authors.lastname: Mersch
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Goepelt
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Brockmeier
authors.affiliation: Institut für Physiologie, Universität Duisburg-Essen, D45122 Essen, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Metzen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000532:radiotherapy / Q000628:therapy*; D004721:Endoplasmic Reticulum; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D019704:Protein Disulfide-Isomerases / Q000172:deficiency* / Q000235:genetics; D011839:Radiation, Ionizing; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D016159:Tumor Suppressor Protein p53; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human
keywords: ER chaperone; apoptosis; endoplasmic reticulum; p53; unfolded protein response