Depletion of the thiol oxidoreductase ERp57 in tumor cells inhibits proliferation and increases sensitivity to ionizing radiation and chemotherapeutics
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Melanie Hussmann1,*, Kirsten Janke1,*, Philip Kranz1, Fabian Neumann1, Evgenija Mersch1, Melanie Baumann1, Kirsten Goepelt1, Ulf Brockmeier1, Eric Metzen1
1Institut für Physiologie, Universität Duisburg-Essen, Hufelandstraße 55, D45122 Essen, Germany
*These authors have contributed equally to this work
Eric Metzen, e-mail: [email protected]
Keywords: endoplasmic reticulum, ER chaperone, unfolded protein response, p53, apoptosis
Received: July 15, 2015 Accepted: October 08, 2015 Published: October 21, 2015
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.
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