Tongzheng Liu¹, Yuan Fang², Haoxing Zhang^1,3, Min Deng¹, Bowen Gao¹, Nifang Niu⁴, Jia Yu³, SeungBaek Lee¹, JungJin Kim¹, Bo Qin¹, Fang Xie⁴,Debra Evans¹, Liewei Wang⁴, Wenhui Lou^2,*, and Zhenkun Lou^1,*

Author Affiliations

↵*Corresponding Authors:
Zhenkun Lou, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-2702; Fax: 507-293-0107; E-mail: lou.zhenkun@mayo.edu; and Wenhui Lou, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. E-mail: lou.wenhui@zs-hospital.sh.cn   T. Liu and Y. Fang contributed equally to this article.

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.

The copyright reseverd by Cancer Res; 76(3); 572–81. ©2015 AACR. Please log on Cancer Res to view the full text. http://cancerres.aacrjournals.org/content/76/3/572.abstract