GRP78 regulates sensitivity of human colorectal cancer cells to DNA targeting agents

Abstract

This study was carried out to investigate the activation status of unfolded protein response (UPR) in colorectal cancer (CRC) and its contribution to CRC resistance to chemotherapy-induced apoptosis. Chemotherapy-induced apoptosis was assessed by the propidium iodide method. Activation of UPR was evaluated in CRC cell lines using immunoblotting technique and in CRC tissues using immunohistochemistry. Findings of the present study revealed that the UPR is constitutively activated in CRC cell lines and CRC tissues isolated from patients, as evidenced by relatively high levels of the 78-kDa glucose-regulated protein (GRP78) and spliced X-box-binding protein 1 mRNA in tissue samples. In addition, CRC cell lines differentially responded to clinically relevant DNA-targeting agents including cisplatin, and 5-flourouracil. Moreover, the levels of GRP78 were inversely associated with sensitivity of CRC cells to chemotherapy-induced apoptosis. Inhibition of GRP78 by siRNA resulted in increased sensitivity of CRC cells to chemotherapeutic agents. Collectively, current results appear to provide novel insights into the role of UPR in determining sensitivity of CRC cells to chemotherapeutic agents and might have important implications for personalized CRC treatment.

Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

“… 45 For instance, increased expression levels of major actors of the UPR such as IRE1α, unspliced and spliced XBP1, PERK and ATF6 were observed in tissues sections from a variety of human tumors including brain, breast, gastric, kidney, liver, lung and pancreatic cancers ( Table 1 ). 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 Moreover, the chaperone GRP78 is also found overexpressed in many cancers 46 , 47 , 48 , 49 , 50 , 51 , 52 , 54 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 64 , 65 , 66 and is involved in the dissemination/metastasis of human tumors. GRP78 overexpression is associated with higher tumor grades and reduced patients’ survival.…”

Endoplasmic reticulum ribosome-binding protein 1, RRBP1, promotes progression of colorectal cancer and predicts an unfavourable prognosis

“…Moreover, ER stress may also trigger autophagy progression ( Yorimitsu et al , 2006 ; Ciechomska et al , 2013 ). Unfolded protein response signalling molecules, such as immunoglobulin heavy-chain binding protein (BIP; also known as GRP78 and HSP5A), heat shock protein 90 kDa beta (HSP90B1; also known as GRP94) and C/EBP homologous protein (CHOP; also known as DDIT3 and GADD153), have been reported to regulate the chemo- and radio-sensitivities of CRC cells ( Mhaidat et al , 2014 ; Drake et al , 2015 ), and to be correlated with CRC ( Rask et al , 2000 ; Xing et al , 2006 ; Takahashi et al , 2011 ). Notably, BIP, a key molecule in UPR signalling, has been identified as a novel predictive biomarker for CRC patients to receive adjuvant chemoradiotherapy ( Thornton et al , 2013 ; Lee et al , 2015 ).…”

Potassium-3-beta-hydroxy-20-oxopregn-5-en-17-alpha-yl sulfate: a novel inhibitor of 78 kDa glucose-regulated protein

“… 11 In addition, a significant association was found between GRP78 expression and response to chemotherapy. 12 Moreover, GRP78 was found to be constitutively activated in CRC cell lines and CRC tissues isolated from patients. 26 Furthermore, levels of GRP78 were inversely associated with sensitivity of CRC cells to chemotherapy-induced apoptosis.…”

“…It has been shown that transcriptional inhibition of GRP78 by siRNA increases in vitro and in vivo chemotherapy-induced cell death. 12 , 27 In addition, inhibition of GRP78 by using nucleoside analogs has been shown to inhibit cancer cell proliferation. 10 This was due to binding of these analogs to the ATPase domain of GRP78 and resulted in enhanced synthesis of procaspases, thus enhancing apoptotic cell death.…”

“…For example, the constitutive expression of GRP78 in SW480 cells was higher than that in the chemotherapy sensitive HCT116 cells. 11 , 12 The rationale of the present study was to study the active site of GRP78 inhibitors utilizing computer-aided drug design techniques. Based on computer modeling, the active site will be subjected to mapping procedure using structure-based pharmacophore modeling in Discovery Studio 3.5 based on commercially available compound database.…”