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. 2013 Feb 11:4:10.
doi: 10.3389/fphar.2013.00010. eCollection 2013.

The Molecular Chaperone GRP78/BiP in the Development of Chemoresistance: Mechanism and Possible Treatment

Corinna Roller  1 , Danilo Maddalo
Affiliations

The Molecular Chaperone GRP78/BiP in the Development of Chemoresistance: Mechanism and Possible Treatment

Corinna Roller et al. Front Pharmacol. .

Abstract

Treatment of several types of cancer such as lung, breast, prostate, and pancreas has shown notable progresses in the past decades. However, after an initial response, tumors eventually became resistant to chemotherapy. This phenomenon, known as chemoresistance, accounts for the death of most cancer patients. Several studies in patients refractory to therapy have revealed the upregulation of the molecular chaperone GRP78/Binding Protein, BiP (BiP) both at the RNA and protein expression level. Furthermore GRP78/BiP relocates to the cell membrane in malignant but not in benign cells. In this communication we review studies on the role and the mechanism of action of GRP78/BiP during development of chemoresistance in cancer cells. In addition we discuss the possible role of GRP78 as a biomarker and as a target in cancer therapy.

Keywords: cell stress; chaperone; drug resistance; therapy; unfolded protein response.

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Figures

Figure 1
Figure 1
BiP as master regulator of the Unfolded Protein Response. Upon accumulation of unfolded peptides in the Endoplasmic Reticulum (ER) the chaperone BiP is titrated away from the stress sensors PKR-like ER kinase (PERK), inositol-requiring protein 1 (IRE1) and activating transcription factor 6 (ATF6). When released by BiP, PERK homodimerizes and autophosphorylates before phosphorylating the alpha subunit of the eukaryotic initiation factor 2 (eIF2α). eIF2α phosphorylation inhibits transcription while activating the transcription factor ATF4 and its target gene C/EBP homologous protein (CHOP). CHOP induces apoptosis by suppressing Bcl-2 and activating Bim and Bax gene expression. Similarly to PERK, the kinase/endonuclease IRE1 homodimerizes and autophosphorylates before splicing Xbp1 mRNA (Xbp1u: Xbp1 unspliced; Xbp1s: Xbp1 spliced). The third branch of the UPR is activated after cleavage of the transcription factor ATF6 in the Golgi (cATF6). Both cATF6 and Xbp1s regulate transcription of pro-survival genes like Glucose Regulated Proteins 78 and 94 (GRP78 and 94) and Protein Disulfide Isomerases (PDIs). In addition to its canonical function in the ER, it has also been shown that BiP can localize to the plasma membrane and regulate the Akt/PI3K pathway. (Yellow dots indicate phosphorylation. For simplicity PERK and IRE1 are shown as monomers).
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