eIF4E binding protein 1 expression is associated with clinical survival outcomes in colorectal cancer

// Min-Wu Chao 1 , Li-Ting Wang 1 , Chin-Yu Lai 1 , Xiao-Ming Yang 2 , Ya-Wen Cheng 4 , Kuo-Hsiung Lee 2, 3 , Shiow-Lin Pan 4, 5, * , Che-Ming Teng 1, * 1 Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 3 Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan 4 The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 5 Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Shiow-Lin Pan, e-mail: slpan@tmu.edu.tw Che-Ming Teng, e-mail: cmteng@ntu.edu.tw Keywords: colorectal cancer (CRC), eIF4E binding protein 1, hypoxia, prognosis, YXM110 Received: March 10, 2015 Accepted: June 19, 2015 Published: June 29, 2015 ABSTRACT eIF4E binding protein 1 (4E-BP1), is critical for cap-dependent and cap-independent translation. This study is the first to demonstrate that 4E-BP1 expression correlates with colorectal cancer (CRC) progression. Compared to its expression in normal colon epithelial cells, 4E-BP1 was upregulated in CRC cell lines and was detected in patient tumor tissues. Furthermore, high 4E-BP1 expression was statistically associated with poor prognosis. Hypoxia has been considered as an obstacle for cancer therapeutics. Our previous data showed that YXM110, a cryptopleurine derivative, exhibited anticancer activity via 4E-BP1 depletion. Here, we investigated whether YXM110 could inhibit protein synthesis under hypoxia. 4E-BP1 expression was notably decreased by YXM110 under hypoxic conditions, implying that cap-independent translation could be suppressed by YXM110. Moreover, YXM110 repressed hypoxia-inducible factor 1α (HIF-1α) expression, which resulted in decreased downstream vascular endothelial growth factor (VEGF) expression. These observations highlight 4E-BP1 as a useful biomarker and therapeutic target, indicating that YXM110 could be a potent CRC therapeutic drug.