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.
Highlights
One of the major challenges of current cancer treatment is the resistance of tumor cells to ionizing radiation (IR) and chemotherapeutical substances
Reduced apoptosis correlated with reduced Bax protein levels in MDA-MB-231 which is in line with the differing effects on apoptosis induction
One metabolic trait which distinguishes most tumor cells from normal cells is that, despite harsh microenvironmental conditions such as hypoxia, nutrient deprivation and low pH, they must synthesize proteins at a high rate and show an upregulation of the endoplasmic reticulum (ER) folding machinery per se which leads to continuous perturbation of the ER and activation of ER-associated degradation pathway (ERAD)
Summary
One of the major challenges of current cancer treatment is the resistance of tumor cells to ionizing radiation (IR) and chemotherapeutical substances. One survival mechanism of cells under stress conditions is the activation of the Unfolded Protein. Response (UPR) through one of its three ER-stress sensors IRE1, PERK and ATF6. Activation of the UPR can occur after general and reversible attenuation of protein synthesis via eIF2α phosphorylation which is summarized as the Integrated Stress Response (ISR) [7]. Activation of the ISR results in the synthesis of UPR target genes through increased eIF2α-independent translation of the transcription factor ATF4. The knockdown of BiP enhanced doxorubicininduced apoptosis in proliferating HEp3 cells, and in a dormant subgroup which usually shows high resistance to chemotherapeutic treatment [11]
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