ERp29 regulates response to doxorubicin by a PERK-mediated mechanism

Abstract

ERp29 is an endoplasmic reticulum (ER) luminal protein with a putative secretion factor/escort chaperone function. Accumulated evidence has implicated ERp29 in the thyroglobulin secretion, polyoma virus transport and recently in carcinogenesis. ERp29 levels were elevated in the tumors of various origins and under the conditions of genotoxic stress, such as ionizing radiation. Here we report the induction of ERp29 during the treatment of cells with doxorubicin, a commonly used antineoplastic agent. Experiments in the p53 -/- cells and p53 knockout mouse revealed that doxorubicin effect on ERp29 is p53 dependent. The increase of ERp29 level appears to activate a negative feedback loop where the elevated amounts of ERp29 augment cell viability as shown by a clonogenic cell survival assay. To elucidate the mechanisms behind the doxorubicin effects we have studied the impact of ERp29 on the interaction with the ER stress-activated eukaryotic translation initiation factor 2-alpha kinase 3 (PERK) that was shown to facilitate tumor cells' resistance to drug toxicity. Co-immunoprecipitation demonstrated physical interaction of ERp29 with PERK and moreover, overexpression of ERp29 enhanced endogenous levels of PERK. Our results identify ERp29 as a novel regulator of PERK and provide evidence for the role of ER resident factors in the regulation of chemotherapeutic efficacy. These findings show that PERK may represent a nodal point between ER stress and chemotherapeutic response.

Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

“…Indeed, treatment of A549 lung and HepG2 liver cancer-bearing mice with TUN strongly inhibited tumor growth and prolonged the survival of the experimental mice in association with DOX, which confirms and extends earlier results revealing the chemosensitizing activity of ER-stress induction (Farmaki et al 2011, Firczuk et al 2013, Ahmad et al 2014, Liu et al 2014.…”

“…ER stress is involved in various pathologic conditions, while its modulation increasingly appears to have therapeutic value for several conditions including cancer (Farmaki et al 2011, Firczuk et al 2013, Ahmad et al 2014, Liu et al 2014). An important aspect of ER stress and subsequent UPR is the regulation of the balance between the prosurvival (adaptive) and pro-apoptotic mode of action.…”

Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases

“…GC-rich sequence, lack of a TATA-box, multiple transcription start sites) of a constitutively expressed housekeeping gene (Sargsyan et al 2002a). Furthermore, recent evidence shows that ERp29 interacts with, and regulates, PERK (Farmaki et al 2011) and ATF6 (Hirsch et al 2014), two important branches of the UPR pathways. Overexpression of ERp29 increases total PERK protein level without altering PERK phosphorylation (Farmaki et al 2011).…”

“…Furthermore, recent evidence shows that ERp29 interacts with, and regulates, PERK (Farmaki et al 2011) and ATF6 (Hirsch et al 2014), two important branches of the UPR pathways. Overexpression of ERp29 increases total PERK protein level without altering PERK phosphorylation (Farmaki et al 2011). Deletion of ERp29 selectively impairs the activation of ATF6 and CHOP, but has no effect on other UPR branches, such as the PERK downstream activating transcription factor 4 (ATF4) and eukaryotic initiation factor 2 alpha (eIF2α), and the X-box binding protein 1 (XBP1) pathways (Hirsch et al 2014).…”

ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK

“…6 Significantly, overexpression of ERp29 increases cell survival when cells are exposed to genotoxic stress induced by doxorubicin and radiation treatment. [7][8][9] These studies indicate a pivotal role of ERp29 in inducing cell growth arrest and cell survival. However, the detailed mechanisms involved remain unknown.…”