Journal article
HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy
Cancer research (Chicago, Ill.), Vol.76(3), pp.572-581
02/01/2016
DOI: 10.1158/0008-5472.CAN-15-0671
PMCID: PMC4737988
PMID: 26676747
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. (C)2015 AACR.
Details
- Title: Subtitle
- HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy
- Creators
- Tongzheng Liu - Mayo ClinicYuan Fang - Fudan UniversityHaoxing Zhang - Southwest UniversityMin Deng - Mayo ClinicBowen Gao - Mayo ClinicNifang Niu - Mayo ClinicJia Yu - Southwest UniversitySeungBaek Lee - Mayo Clin, Div Oncol Res, Dept Oncol, Rochester, MN USAJungJin Kim - Mayo Clin, Div Oncol Res, Dept Oncol, Rochester, MN USABo Qin - Mayo ClinicFang Xie - Mayo ClinicDebra Evans - Mayo ClinicLiewei Wang - Mayo ClinicWenhui Lou - Fudan UniversityZhenkun Lou - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.76(3), pp.572-581
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/0008-5472.CAN-15-0671
- PMID
- 26676747
- PMCID
- PMC4737988
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Number of pages
- 10
- Grant note
- CA130996; CA189666; CA148940 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA130996 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 201202007 / Special Research Fund for public welfare from Ministry of Health of China
- Language
- English
- Date published
- 02/01/2016
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701544302771
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