title: HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy.
abstract: Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the less studied gene HEAT repeat-containing protein 1 (HEATR1) as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these findings, treatment with the AKT inhibitor triciribine sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment, and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients.
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota. School of Life Sciences, Southwest University, Chongqing, China.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Bowen
authors.initials: B
authors.lastname: Gao
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nifang
authors.initials: N
authors.lastname: Niu
authors.affiliation: School of Life Sciences, Southwest University, Chongqing, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: SeungBaek
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: JungJin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Debra
authors.initials: D
authors.lastname: Evans
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. lou.zhenkun@mayo.edu lou.wenhui@zs-hospital.sh.cn.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Lou
authors.affiliation: Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota. lou.zhenkun@mayo.edu lou.wenhui@zs-hospital.sh.cn.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011897:Random Allocation; D012263:Ribonucleosides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C000597348:HEATR1 protein, human; D015778:Minor Histocompatibility Antigens; D016601:RNA-Binding Proteins; D012263:Ribonucleosides; D003841:Deoxycytidine; C023764:triciribine; D051058:Oncogene Protein v-akt; D000093542:Gemcitabine