Expression of GRP78, Master Regulator of the Unfolded Protein Response, Increases Chemoresistance in Pancreatic Ductal Adenocarcinoma

Abstract

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is dismal. Although gemcitabine (GEM) is the standard chemotherapeutic agent for adjuvant therapy of resectable PDAC, recurrent disease is observed in an alarming number of GEM-treated patients. Regardless of the adjuvant therapy, the vast majority of patients treated with chemotherapy after surgical resection show tumor recurrence. A better understanding of the molecular mechanisms that contribute to chemoresistance would aid the development of more effective treatment strategies. GRP78 is an endoplasmic reticulum (ER) chaperone protein that primarily resides in the lumen of the ER and is the master regulator of the unfolded protein response (UPR). Here, we report that expression of GRP78 is significantly higher in GEM-resistant PDAC compared to GEM-sensitive PDAC patient samples. We show that GRP78 induces chemoresistance in PDAC cells. Our results also show that knockdown of GRP78 reduces chemoresistance in PDAC. Finally, we found that IT-139, a ruthenium-based anticancer drug, can overcome GRP78-mediated chemoresistance. In vitro, IT-139 restores sensitivity to cytotoxic drugs in drug-resistant PDAC cells and induces twice as much cell death in combination treatment compared with GEM alone. In vivo, a single weekly IT-139 treatment in combination with GEM caused a 35% increase in median survival and a 25% increase in overall survival compared to GEM alone. Collectively, our data show that GRP78 expression promotes chemoresistance in PDAC and therapeutic strategies, blocking the activity of GRP78 increases the efficacy of currently available therapies.

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

“…Additionally, we found GRP78 to be overexpressed in the ducts/pseudoducts of patient biopsy punches, which is consistent with recently published studies (Fig. 1E) (Gifford et al ., 2016; Niu et al ., 2015). …”

“…GRP78, one of the regulators of the UPR, is an attractive target because it is responsible for maintaining homeostasis in the ER. Recently, a small molecule GRP78 inhibitor called IT‐139 was shown to sensitize chemoresistant PDAC cells to gemcitabine (Gifford et al ., 2016). Our previously published data shows that GRP78‐mediated ER homeostasis is dependent on SP1 activity and inhibition of SP1 prevents the homeostasis and pushes the UPR to a chronic ER stress phase, leading to cancer cell death (Dauer et al ., 2017).…”

“…GRP78, the regulator of the UPR, has previously been correlated with poor patient prognosis in multiple cancers, including pancreatic cancer (Avril et al ., 2017; Gifford et al ., 2016; Ma and Hendershot, 2004; Niu et al ., 2015; Wang and Kaufman, 2014). Based on correlation studies and direct overexpression leading to chemoresistance, numerous proteins in the UPR pathway have been targeted with small molecules in hopes to attenuate chemoresistance (Chevet et al ., 2015; Gifford et al ., 2016; Lee, 2014; Roller and Maddalo, 2013). In spite of a generous body of literature correlating chemoresistance to expression of genes involved in UPR, there have been almost no studies to elucidate the mechanism(s) by which UPR contributes to chemoresistance.…”

“…It was recently reported that GRP78 correlates with poor prognosis and chemoresistance in pancreatic cancer (Gifford et al ., 2016; Niu et al ., 2015). Further, it was shown that gemcitabine‐resistant cell lines have higher GRP78 expression compared to gemcitabine‐sensitive cell lines (Gifford et al ., 2016).…”

“…It was recently reported that GRP78 correlates with poor prognosis and chemoresistance in pancreatic cancer (Gifford et al ., 2016; Niu et al ., 2015). Further, it was shown that gemcitabine‐resistant cell lines have higher GRP78 expression compared to gemcitabine‐sensitive cell lines (Gifford et al ., 2016). It has also been reported that patients with pancreatic cancer have an upregulation of ABC transporters, particularly ABCC3 and ABCC5 (Konig et al ., 2005; Pang et al ., 2014).…”