HEATR1 negatively regulates akt to help sensitize pancreatic cancer cells to chemotherapy

Tongzheng Liu, Yuan Fang, Haoxing Zhang, Min Deng, Bowen Gao, Nifang Niu, Jia Yu, Seung Baek Lee, Jung Jin Kim, Bo Qin, Fang Xie, Debra Evans, Liewei Wang, Wenhui Lou, Zhenkun Lou

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)572-581
Number of pages10
JournalCancer research
Volume76
Issue number3
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Liu, T., Fang, Y., Zhang, H., Deng, M., Gao, B., Niu, N., Yu, J., Lee, S. B., Kim, J. J., Qin, B., Xie, F., Evans, D., Wang, L., Lou, W., & Lou, Z. (2016). HEATR1 negatively regulates akt to help sensitize pancreatic cancer cells to chemotherapy. Cancer research, 76(3), 572-581. https://doi.org/10.1158/0008-5472.CAN-15-0671