title: 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. Mol Cancer Ther; 15(5); 1043-52. ©2016 AACR.
authors.affiliation: Department of Biological Sciences, University of Notre Dame, South Bend, Indiana. Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Jenifer B
authors.initials: JB
authors.lastname: Gifford
authors.affiliation: Department of Biological Sciences, University of Notre Dame, South Bend, Indiana. Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana. Integrated Biomedical Sciences Program, University of Notre Dame, South Bend, Indiana.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Zeleniak
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles California.
authors.forename: Antreas
authors.initials: A
authors.lastname: Hindoyan
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles California. School of Life Sciences, Peking University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Surgery, University of California, Los Angeles, Los Angeles, California.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
authors.affiliation: Department of Biological Sciences, University of Notre Dame, South Bend, Indiana. Harper Cancer Research Institute, University of Notre Dame, South Bend, Indiana. rhill3@nd.edu.
authors.forename: Reginald
authors.initials: R
authors.lastname: Hill
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D056811:Unfolded Protein Response; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D003841:Deoxycytidine; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine