Zengxun Li1, Yi Ge1, Jie Dong1, Hongwei Wang1, Tiansuo Zhao1, Xiuchao Wang1, Jing Liu1, Song Gao1, Lei Shi2, Shengyu Yang3, Chongbiao Huang4, Jihui Hao5. 1. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. 2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. 3. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania. 4. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. Electronic address: chhuang@tmu.edu.cn. 5. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China. Electronic address: haojihui@tjmuch.com.
Abstract
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by severe metabolic stress due to fibrosis and poor vascularization. BZW1 is an eIF5-mimic protein involved in tumorigenesis and progression. The aim of this study was to investigate the role of BZW1 in metabolic stress resistance in PDAC. METHODS: BZW1 expression was evaluated in human PDAC tissue microarray and PDAC cells. Glycolysis regulation of BZW1 and its correlation with glycolysis-related genes was analyzed. Tumor growth, cell proliferation, and apoptosis were evaluated in mice xenograft tumors and patient-derived organoids. RESULTS: The results of bioinformatic screening identified that BZW1 was 1 of the top 3 genes favorable for tumor progression in PDAC. The analysis of our cohort confirmed that BZW1 was overexpressed in human PDAC tissues compared with nontumor tissues, and its abnormal expression was correlated with large tumor size and poor prognosis. BZW1 promoted cell proliferation and inhibited apoptosis in both mouse xenograft models and PDAC-derived organoids via facilitating glycolysis in the oxygen-glucose-deprivation condition. Mechanically, BZW1 served as an adaptor for PKR-like endoplasmic reticulum (ER) kinase (PERK), facilitated the phosphorylation of eIF2α, promoted internal ribosome entry site-dependent translation of HIF1α and c-Myc, and thereby boosted the Warburg effect. In organoid-based xenografts with high BZW1 levels, both the PERK/eIF2α phosphorylation inhibitor GSK2606414 and ISRIB significantly suppressed tumor growth and prolonged animal survival. CONCLUSIONS: BZW1 is a key molecule in the internal ribosome entry site-dependent translation of HIF1α/c-Myc and plays crucial roles in the glycolysis of PDAC. BZW1 might serve as a therapeutic target for patients with pancreatic cancer.
BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is characterized by severe metabolic stress due to fibrosis and poor vascularization. BZW1 is an eIF5-mimic protein involved in tumorigenesis and progression. The aim of this study was to investigate the role of BZW1 in metabolic stress resistance in PDAC. METHODS: BZW1 expression was evaluated in human PDAC tissue microarray and PDAC cells. Glycolysis regulation of BZW1 and its correlation with glycolysis-related genes was analyzed. Tumor growth, cell proliferation, and apoptosis were evaluated in mice xenograft tumors and patient-derived organoids. RESULTS: The results of bioinformatic screening identified that BZW1 was 1 of the top 3 genes favorable for tumor progression in PDAC. The analysis of our cohort confirmed that BZW1 was overexpressed in human PDAC tissues compared with nontumor tissues, and its abnormal expression was correlated with large tumor size and poor prognosis. BZW1 promoted cell proliferation and inhibited apoptosis in both mouse xenograft models and PDAC-derived organoids via facilitating glycolysis in the oxygen-glucose-deprivation condition. Mechanically, BZW1 served as an adaptor for PKR-like endoplasmic reticulum (ER) kinase (PERK), facilitated the phosphorylation of eIF2α, promoted internal ribosome entry site-dependent translation of HIF1α and c-Myc, and thereby boosted the Warburg effect. In organoid-based xenografts with high BZW1 levels, both the PERK/eIF2α phosphorylation inhibitor GSK2606414 and ISRIB significantly suppressed tumor growth and prolonged animal survival. CONCLUSIONS: BZW1 is a key molecule in the internal ribosome entry site-dependent translation of HIF1α/c-Myc and plays crucial roles in the glycolysis of PDAC. BZW1 might serve as a therapeutic target for patients with pancreatic cancer.
Authors: Haoqiang Ying; Alec C Kimmelman; Costas A Lyssiotis; Sujun Hua; Gerald C Chu; Eliot Fletcher-Sananikone; Jason W Locasale; Jaekyoung Son; Hailei Zhang; Jonathan L Coloff; Haiyan Yan; Wei Wang; Shujuan Chen; Andrea Viale; Hongwu Zheng; Ji-hye Paik; Carol Lim; Alexander R Guimaraes; Eric S Martin; Jeffery Chang; Aram F Hezel; Samuel R Perry; Jian Hu; Boyi Gan; Yonghong Xiao; John M Asara; Ralph Weissleder; Y Alan Wang; Lynda Chin; Lewis C Cantley; Ronald A DePinho Journal: Cell Date: 2012-04-27 Impact factor: 41.582