|
1
|
Zha HL, Chen W, Shi W, Liao YY. Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib Resistance in Gastric Cancer. Curr Med Sci 2023; 43:927-934. [PMID: 37752406 DOI: 10.1007/s11596-023-2789-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 07/18/2023] [Indexed: 09/28/2023]
Abstract
OBJECTIVE Aberrant activating mutations in cyclin-dependent kinases 4 and 6 (CDK4/6) are common in various cancers, including gastroesophageal malignancies. Although CDK4/6 inhibitors, such as abemaciclib and palbociclib, have been approved for breast cancer treatment, their effectiveness as a monotherapy remains limited for gastroesophageal tumors. The present study explored the underlying mechanism of abemaciclib resistance. METHODS Abemaciclib-resistant gastric cancer cell lines were generated, and the phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E expression was compared between resistant and parental cell lines. In order to analyze the role of eIF4E in cell resistance, siRNA knockdown was employed. The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model. RESULTS The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment. Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition, especially those that were resistant to abemaciclib. Ribavirin, which is an approved anti-viral drug, significantly improved the efficacy of abemaciclib, both in vitro and in vivo, by inhibiting eIF4E. Importantly, ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity. CONCLUSION These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer, proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.
Collapse
Affiliation(s)
- Huo-Long Zha
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Wei Chen
- Department of Critical Care Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China
| | - Wei Shi
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China.
| | - Ying-Ying Liao
- Department of Gastroenterology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China.
| |
Collapse
|
|
2
|
Fernandez A, Monsen PJ, Platanias LC, Schiltz GE. Medicinal chemistry approaches to target the MNK-eIF4E axis in cancer. RSC Med Chem 2023; 14:1060-1087. [PMID: 37360400 PMCID: PMC10285747 DOI: 10.1039/d3md00121k] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/08/2023] [Indexed: 06/28/2023] Open
Abstract
Aberrant translation of proteins that promote cell proliferation is an essential factor that defines oncogenic processes and cancer. The process for ribosomal translation of proteins from mRNA requires an essential initiation step which is controlled by the protein eIF4E, which binds the RNA 5'-cap and forms the eIF4F complex that subsequently translates protein. Typically, eIF4E is activated by phosphorylation on Ser209 by MNK1 and MNK2 kinases. Substantial work has shown that eIF4E and MNK1/2 are dysregulated in many cancers and this axis has therefore become an active area of interest for developing new cancer therapeutics. This review summarizes and discusses recent work to develop small molecules that target different steps in the MNK-eIF4E axis as potential cancer therapeutics. The aim of this review is to cover the breadth of different molecular approaches being taken and the medicinal chemistry basis for their optimization and testing as new cancer therapeutics.
Collapse
Affiliation(s)
- Ann Fernandez
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
| | - Paige J Monsen
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
| | - Leonidas C Platanias
- Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA
- Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University Chicago IL 60611 USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center Chicago IL 60612 USA
| | - Gary E Schiltz
- Department of Chemistry, Northwestern University Evanston IL 60208 USA
- Robert H. Lurie Comprehensive Cancer Center Chicago IL 60611 USA
- Department of Pharmacology, Northwestern University Feinberg School of Medicine Chicago IL 60611 USA
| |
Collapse
|
|
3
|
Expression of eIF4E Gene in Glioma and Its Sensitivity to Oxidative Stress. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:5413035. [PMID: 36225177 PMCID: PMC9550436 DOI: 10.1155/2022/5413035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022]
Abstract
Objective Increased expression of eIF4E has been observed in various cancers, which makes eIF4E an attractive target of anticancer drugs. This study mainly discussed eIF4E gene expression in glioma and its sensitivity to oxidative stress (OS). Methods Relevant data from The Cancer Genome Atlas (TCGA) database regarding eIF4E gene expression and its prognostic significance in glioma samples were analyzed. Additionally, we measured eIF4E at mRNA and protein levels in clinical samples collected between July 2019 and September 2021, as well as glioma cell strains. U251 cells cultured in vitro were treated with OS injury induced by hydrogen peroxide (H2O2) and then transfected with si-eIF4E to determine changes in cell multiplication, invasiveness, and migration capacities as well as apoptosis rate. ELISA quantified cell malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) concentrations, and flow cytometry measured reactive oxygen species (ROS) level. Results In glioma samples from the TCGA database, eIF4E showed obviously elevated levels in LGG and GBM patients, which was usually associated with adverse patient prognosis (P < 0.05). eIF4E was also upregulated in glioma cell strains than in HBE cells. In comparison with the blank control group, transfection of si-eIF4E statistically suppressed the capacity of U251 cells to proliferate, invade and migrate, and enhance apoptosis rate, while reducing SOD and GSH-Px and increasing MDA and ROS. In addition, H2O2 induced the upregulation of eIF4E in U251 cells. H2O2 + si-eIF4E exhibited reduced multiplication and number of clone cell formation, invasion, and migration of U251 cells, as well as increased apoptosis rate than H2O2 + si-NC group. Conclusions eIF4E is highly expressed in glioma. Knocking down eIF4E can effectively inhibit the capacity of U251 to proliferate, invade and migrate, and significantly increase apoptosis. In addition, eIF4E knock-down is able to lower OS reaction under H2O2 inducement and enhance U251 cells' sensitivity to OS.
Collapse
|
|
4
|
Yang X, Liu Z, Yin X, Zeng Y, Guo G. Inhibition MNK-eIF4E-β-catenin preferentially sensitizes gastric cancer to chemotherapy. Fundam Clin Pharmacol 2022; 36:712-720. [PMID: 35048413 DOI: 10.1111/fcp.12759] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/30/2021] [Accepted: 01/17/2022] [Indexed: 12/14/2022]
Abstract
Aberrant activation of eIF4E contributes to gastric cancer growth and resistance. MAPK-interacting kinases (MNKs) regulate eIF4E phosphorylation and activity in tumor but not normal cells and are potentially safe targets for the treatment of various cancers. Our work reveals that tomivosertib, a potent and highly selective dual MNK1/2 inhibitor, preferentially sensitizes gastric cancer to chemotherapy via suppressing MNK-eIF4E-β-catenin. We firstly demonstrate that tomivosertib displays higher efficacy than other MNK inhibitors in inhibiting gastric cancer cells. In addition, tomivosertib significantly augments the inhibitory effects of 5-FU and paclitaxel but not everolimus, suggesting that tomivosertib preferentially sensitizes gastric cancer to chemotherapy. We next show that eIF4E overexpression and phosphorylation coordinately regulate β-catenin signaling in gastric cancer. Rescue studies confirm that tomivosertib inhibits gastric cancer via targeting MNK- eIF4E-β-catenin. Finally, we demonstrate that the in vitro functional and mechanism observations are translatable to in vivo gastric cancer model in mice. Tomivosertib is now in Phase 2 clinical trials. Our study provides preclinical evidence to initialize clinical trials for gastric cancer using tomivosertib in combination with chemotherapy.
Collapse
Affiliation(s)
- Xiaolin Yang
- Department of Gastroenterology and Urology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Zhenyang Liu
- Department of Gastroenterology and Urology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Xianli Yin
- Department of Gastroenterology and Urology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yidong Zeng
- Department of Gastroenterology and Urology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Geyang Guo
- Department of Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| |
Collapse
|
|
5
|
Lehman SL, Wilson ED, Camphausen K, Tofilon PJ. Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization. Int J Mol Sci 2021; 22:ijms221910664. [PMID: 34639005 PMCID: PMC8508945 DOI: 10.3390/ijms221910664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/22/2021] [Accepted: 09/29/2021] [Indexed: 01/04/2023] Open
Abstract
Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care.
Collapse
|
|
6
|
Role of RONS and eIFs in Cancer Progression. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5522054. [PMID: 34285764 PMCID: PMC8275427 DOI: 10.1155/2021/5522054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 04/19/2021] [Accepted: 05/14/2021] [Indexed: 12/05/2022]
Abstract
Various research works have piled up conflicting evidence questioning the effect of oxidative stress in cancer. Reactive oxygen and nitrogen species (RONS) are the reactive radicals and nonradical derivatives of oxygen and nitrogen. RONS can act as a double-edged weapon. On the one hand, RONS can promote cancer initiation through activating certain signal transduction pathways that direct proliferation, survival, and stress resistance. On the other hand, they can mitigate cancer progression via their resultant oxidative stress that causes many cancer cells to die, as some recent studies have proposed that high RONS levels can limit the survival of cancer cells during certain phases of cancer development. Similarly, eukaryotic translation initiation factors are key players in the process of cellular transformation and tumorigenesis. Dysregulation of such translation initiation factors in the form of overexpression, downregulation, or phosphorylation is associated with cancer cell's altering capability of survival, metastasis, and angiogenesis. Nonetheless, eIFs can affect tumor age-related features. Data shows that alternating the eukaryotic translation initiation apparatus can impact many downstream cellular signaling pathways that directly affect cancer development. Hence, researchers have been conducting various experiments towards a new trajectory to find novel therapeutic molecular targets to improve the efficacy of anticancer drugs as well as reduce their side effects, with a special focus on oxidative stress and initiation of translation to harness their effect in cancer development. An increasing body of scientific evidence recently links oxidative stress and translation initiation factors to cancer-related signaling pathways. Therefore, in this review, we present and summarize the recent findings in this field linking certain signaling pathways related to tumorigeneses such as MAPK and PI3K, with either RONS or eIFs.
Collapse
|
|
7
|
Zhai S, Lin S, Lin Z, Xu J, Ji T, Chen K, Wu K, Liu H, Ying H, Fei W, Wang J, Fu G, Wang Y, Hu X, Cai X. eIF4EBP3 was downregulated by methylation and acted as a tumor suppressor by targeting eIF4E/β-catenin in gastric cancer. Gastric Cancer 2020; 23:483-496. [PMID: 31853750 DOI: 10.1007/s10120-019-01030-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 11/29/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Epigenetic aberrations of tumor suppressor genes (TSGs), particularly DNA methylation, are frequently involved in the pathogenesis of gastric cancer (GC). Through a methylome study, we identified eIF4EBP3 as a methylated gene in GC. However, the role of eIF4EBP3 in GC progression has not been explored. METHODS The expression and promoter region methylation of eIF4EBP3 in GC and healthy tissues were analyzed in public datasets. eIF4EBP3 expression in GC was detected by semi-quantitative RT-PCR, western blot and immunohistochemistry. We also studied epigenetic alterations and functions in GC. The effects of eIF4EBP3 on cell proliferation, migration and invasion were conducted by functional experiments in vitro and in vivo. Label-free proteomic analysis was applied to identify targets of eIF4EBP3. RESULTS The expression level of eIF4EBP3 was downregulated in gastric cancer due to promoter region methylation, and was associated with poor survival and tumor progression. Ectopic expression of eIF4EBP3 significantly inhibited tumor cell growth, migration and invasion both in vitro and in vivo. Label-free proteomic analysis indicated eIF4EBP3 downregulated the protein level of β-catenin, which was confirmed by western blot. Overexpression of β-catenin reversed the inhibitory effects of eIF4EBP3 on cell growth and migration, indicating that eIF4EBP3 acts on GC cells by targeting the eIF4E/β-catenin axis. CONCLUSION These results suggest that eIF4EBP3 is a novel TSG methylated in gastric cancer that may play important roles in GC development and liver metastasis and indicate eIF4EBP3 as a potential metastasis and survival biomarker for GC.
Collapse
Affiliation(s)
- Shuting Zhai
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Shuang Lin
- Department of Lung Transplantation, Department of Thoracic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
| | - Zhongjie Lin
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Tong Ji
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Ke Chen
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Ke Wu
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Hui Liu
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Hanning Ying
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Weiqiang Fei
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Jin Wang
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Guoxiang Fu
- Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China
| | - Yifan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
| | - Xiaotong Hu
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
| | - Xiujun Cai
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China.
| |
Collapse
|
|
8
|
Mohibi S, Chen X, Zhang J. Cancer the'RBP'eutics-RNA-binding proteins as therapeutic targets for cancer. Pharmacol Ther 2019; 203:107390. [PMID: 31302171 DOI: 10.1016/j.pharmthera.2019.07.001] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 07/02/2019] [Indexed: 12/11/2022]
Abstract
RNA-binding proteins (RBPs) play a critical role in the regulation of various RNA processes, including splicing, cleavage and polyadenylation, transport, translation and degradation of coding RNAs, non-coding RNAs and microRNAs. Recent studies indicate that RBPs not only play an instrumental role in normal cellular processes but have also emerged as major players in the development and spread of cancer. Herein, we review the current knowledge about RNA binding proteins and their role in tumorigenesis as well as the potential to target RBPs for cancer therapeutics.
Collapse
Affiliation(s)
- Shakur Mohibi
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, United States
| | - Xinbin Chen
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, United States
| | - Jin Zhang
- Comparative Oncology Laboratory, Schools of Veterinary Medicine and Medicine, University of California at Davis, United States.
| |
Collapse
|
|
9
|
Han B, Yang Y, Chen J, He X, Lv N, Yan R. PRSS23 knockdown inhibits gastric tumorigenesis through EIF2 signaling. Pharmacol Res 2019; 142:50-57. [PMID: 30769097 DOI: 10.1016/j.phrs.2019.02.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/29/2019] [Accepted: 02/05/2019] [Indexed: 02/06/2023]
Abstract
PRSS23 is a newly discovered serine protease that has been associated with tumor progression in various types of cancers. Our previous study showed PRSS23 is down-regulated obviously in Hedgehog pathway blocked gastric cancer cells. However, the correlation between PRSS23 and tumor progression of gastric cancer remains unclear. Here, the role and mechanism of PRSS23 in tumor progression of gastric cancer were determined. PRSS23 protein levels were significantly increased in gastric cancer tissues compared with the paired adjacent normal gastric mucosa tissues. The high expression of PRSS23 correlated strongly with both poor differentiated histology and cancer region of sinus ventriculi. Gastric cancer patients with low PRSS23 expression displayed a better prognosis. In gastric cancer cells, PRSS23 knockdown inhibited cell proliferation and induced apoptosis. In xenograft tumor model, PRSS23 knockdown led to dramatic decreases of the average tumor volume and the average tumor weight. In addition, PRSS23 knockdown suppressed gastric cancer growth through inhibiting EIF2 signaling using gene expression microarray analysis. Taken together, our results suggest PRSS23 is highly associated with human gastric tumorigenesis and progression. PRSS23 knockdown could suppress tumor growth of gastric cancer in vitro and in vivo through inhibiting EIF2 signaling, and EIF4E maybe a potential target of PRSS23. PRSS23 could serve as a potential target for gastric cancer therapy, and also a biomarker for the prediction of prognosis of gastric cancer.
Collapse
Affiliation(s)
- Bing Han
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, China; Institute of Tropical Fruit Trees, Hainan Academy of Agricultural Sciences, Haikou, China
| | - Yang Yang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, China; Guilin Medical University, Guilin, China
| | - Jiang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, China
| | - Xingxing He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, China
| | - Nonghua Lv
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, China.
| | - Runwei Yan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Key Laboratory of Digestive Diseases of Jiangxi Province, Nanchang, China.
| |
Collapse
|
|
10
|
De A, Jacobson BA, Peterson MS, Stelzner ME, Jay-Dixon J, Kratzke MG, Patel MR, Bitterman PB, Kratzke RA. Inhibition of oncogenic cap-dependent translation by 4EGI-1 reduces growth, enhances chemosensitivity and alters genome-wide translation in non-small cell lung cancer. Cancer Gene Ther 2018; 26:157-165. [DOI: 10.1038/s41417-018-0058-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 09/22/2018] [Accepted: 10/20/2018] [Indexed: 12/20/2022]
|
|
11
|
Ge Y, Wu Q, Ma G, Shao W, Liu H, Zhang Q, Xin J, Xue Y, Du M, Zhao Q, Wang M, Chu H, Zhang Z. Hypermethylation of EIF4E promoter is associated with early onset of gastric cancer. Carcinogenesis 2018; 39:66-71. [PMID: 29342273 DOI: 10.1093/carcin/bgx110] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 09/29/2017] [Indexed: 12/14/2022] Open
Abstract
Although gastric cancer (GC) in young adults (≤ 45 years) accounts for fewer than 10% of newly diagnosed cases, the young patients are more likely to have advanced disease at presentation compared with elderly patients. Previous studies have identified that the DNA methylation of genomes are different during aging. Our study aimed to explore the association between DNA methylation and the onset of GC. We applied Illumina HumanMethylation450 BeadChip to examine methylation expression profiles and compared methylation expression patterns in five early onset GC patients and seven elderly patients. Additionally, we evaluated the associations of methylation expression with different clinicopathological characteristics of GC. Our results showed that the pattern of genome-wide methylation expression was significantly different between early onset and elderly GC. The top 10 hypomethylation and hypermethylation CpG sites were selected for further analyses in The Cancer Genome Atlas (TCGA) database. We found that the hypermethylation of cg11037477, located at the promoter of EIF4E, was significantly associated with age at diagnosis and the expression of EIF4E. Besides, GC patients with high level of cg11037477 were more likely to have advance disease with T3/T4 invasion and III/IV stage. The cg11037477 hypermethylation and EIF4E down-expression were significantly related to poor survival of GC patients. Our study provides new insights into the molecular mechanism of early onset patients with GC and suggests that methylation of cg11037477 and expression of EIF4E may act as prognostic markers in GC.
Collapse
Affiliation(s)
- Yuqiu Ge
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qin Wu
- Department of Medical Technology, Yancheng Insititute of Health Sciences, Yancheng, China
| | - Gaoxiang Ma
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Wei Shao
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hanting Liu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qiang Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Junyi Xin
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yao Xue
- Department of Hematology and oncology, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Mulong Du
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Qinghong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haiyan Chu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
12
|
Vaklavas C, Blume SW, Grizzle WE. Translational Dysregulation in Cancer: Molecular Insights and Potential Clinical Applications in Biomarker Development. Front Oncol 2017; 7:158. [PMID: 28798901 PMCID: PMC5526920 DOI: 10.3389/fonc.2017.00158] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 07/06/2017] [Indexed: 01/04/2023] Open
Abstract
Although transcript levels have been traditionally used as a surrogate measure of gene expression, it is increasingly recognized that the latter is extensively and dynamically modulated at the level of translation (messenger RNA to protein). Over the recent years, significant progress has been made in dissecting the complex posttranscriptional mechanisms that regulate gene expression. This advancement in knowledge came hand in hand with the progress made in the methodologies to study translation both at gene-specific as well as global genomic level. The majority of translational control is exerted at the level of initiation; nonetheless, protein synthesis can be modulated at the level of translation elongation, termination, and recycling. Sequence and structural elements and epitranscriptomic modifications of individual transcripts allow for dynamic gene-specific modulation of translation. Cancer cells usurp the regulatory mechanisms that govern translation to carry out translational programs that lead to the phenotypic hallmarks of cancer. Translation is a critical nexus in neoplastic transformation. Multiple oncogenes and signaling pathways that are activated, upregulated, or mutated in cancer converge on translation and their transformative impact "bottlenecks" at the level of translation. Moreover, this translational dysregulation allows cancer cells to adapt to a diverse array of stresses associated with a hostile microenviroment and antitumor therapies. All elements involved in the process of translation, from the transcriptional template, the components of the translational machinery, to the proteins that interact with the transcriptome, have been found to be qualitatively and/or quantitatively perturbed in cancer. This review discusses the regulatory mechanisms that govern translation in normal cells and how translation becomes dysregulated in cancer leading to the phenotypic hallmarks of malignancy. We also discuss how dysregulated mediators or components of translation can be utilized as biomarkers with potential diagnostic, prognostic, or predictive significance. Such biomarkers have the potential advantage of uniform applicability in the face of inherent tumor heterogeneity and deoxyribonucleic acid instability. As translation becomes increasingly recognized as a process gone awry in cancer and agents are developed to target it, the utility and significance of these potential biomarkers is expected to increase.
Collapse
Affiliation(s)
- Christos Vaklavas
- Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Scott W Blume
- Department of Medicine, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - William E Grizzle
- Department of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
| |
Collapse
|
|
13
|
Ali MU, Ur Rahman MS, Jia Z, Jiang C. Eukaryotic translation initiation factors and cancer. Tumour Biol 2017; 39:1010428317709805. [PMID: 28653885 DOI: 10.1177/1010428317709805] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent technological advancements have shown tremendous mechanistic accomplishments in our understanding of the mechanism of messenger RNA translation in eukaryotic cells. Eukaryotic messenger RNA translation is very complex process that includes four phases (initiation, elongation, termination, and ribosome recycling) and diverse mechanisms involving protein and non-protein molecules. Translation regulation is principally achieved during initiation step of translation, which is organized by multiple eukaryotic translation initiation factors. Eukaryotic translation initiation factor proteins help in stabilizing the formation of the functional ribosome around the start codon and provide regulatory mechanisms in translation initiation. Dysregulated messenger RNA translation is a common feature of tumorigenesis. Various oncogenic and tumor suppressive genes affect/are affected by the translation machinery, making the components of the translation apparatus promising therapeutic targets for the novel anticancer drug. This review provides details on the role of eukaryotic translation initiation factors in messenger RNA translation initiation, their contribution to onset and progression of tumor, and how dysregulated eukaryotic translation initiation factors can be used as a target to treat carcinogenesis.
Collapse
Affiliation(s)
- Muhammad Umar Ali
- 1 Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Muhammad Saif Ur Rahman
- 1 Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenyu Jia
- 2 Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, China
| | - Cao Jiang
- 1 Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
14
|
Wu S, Yang L, Wu D, Gao Z, Li P, Huang W, Wang X. AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression. J Cell Mol Med 2017; 21:3481-3493. [PMID: 28661037 PMCID: PMC5706588 DOI: 10.1111/jcmm.13258] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 04/26/2017] [Indexed: 12/19/2022] Open
Abstract
Gastric cancer is the third leading cause of cancer-related deaths worldwide, and patients with lymph node, peritoneal and distant metastasis have a poor prognosis. Overexpression of Astrocyte-elevated gene-1 (AEG-1) has been reported to be correlated with the progression and metastasis of gastric cancer. However, its mechanisms are quite unclear. In this study, we found that elevated expression of AEG-1 was correlated with metastasis in human gastric cancer tissues. Moreover, gain- or loss-of-function of AEG-1, respectively, promoted or suppressed epithelial-mesenchymal transition (EMT), migration and invasion of gastric cancer cells. AEG-1 positively regulated eIF4E, MMP-9 and Twist expression. Manipulating eIF4E expression by transfection of overexpression constructs or siRNAs partially eliminated AEG-1-regulated EMT, cell migration and invasion. In addition, overexpression or knockdown of eIF4E promoted or suppressed EMT, cell migration and invasion in parallel with upregulation of MMP-9 and Twist expression, while manipulating eIF4E expression partially abrogated AEG-1-induced MMP-9 and Twist. Finally, silencing of AEG-1 expression not only inhibited tumour growth in parallel with downregulation of eIF4E, MMP-9 and Twist expression in a xenograft nude mouse model, but also suppressed lymph node and peritoneal metastasis of gastric cancer in an orthotopic nude mouse model. These findings suggest that AEG-1 promotes gastric cancer metastasis through upregulation of eIF4E-mediated MMP-9 and Twist, which provides new diagnostic markers and therapeutic targets for cancer metastasis.
Collapse
Affiliation(s)
- Shengjie Wu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Li Yang
- Department of General Surgery, Medical Oncology and Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dandan Wu
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.,Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China
| | - Zhongyuan Gao
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ping Li
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenbin Huang
- Department of Pathology, Nanjing Medical University Affiliated Nanjing Hospital (Nanjing First Hospital), Nanjing, Jiangsu, China
| | - Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
15
|
Wang L, Arras J, Katsha A, Hamdan S, Belkhiri A, Ecsedy J, El-Rifai W. Cisplatin-resistant cancer cells are sensitive to Aurora kinase A inhibition by alisertib. Mol Oncol 2017; 11:981-995. [PMID: 28417568 PMCID: PMC5537695 DOI: 10.1002/1878-0261.12066] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 03/23/2017] [Accepted: 04/09/2017] [Indexed: 12/13/2022] Open
Abstract
De novo and acquired resistance to platinum therapy such as cisplatin (CDDP) is a clinical challenge in gastric cancer treatment. Aberrant expression and activation of aurora kinase A (AURKA) and eukaryotic translation initiation factor 4E (eIF4E) are detected in several cancer types. Herein, we investigated the role of AURKA in CDDP resistance in gastric cancer. Western blot analysis demonstrated overexpression of AURKA and phosphorylation of eIF4E in acquired and de novo CDDP‐resistant gastric cancer models. Inhibition of AURKA with MLN8237 (alisertib) alone or in combination with CDDP significantly suppressed viability of CDDP‐resistant cancer cells (P < 0.01). Additionally, inhibition or knockdown of AURKA decreased protein expression of p‐eIF4E (S209), HDM2, and c‐MYC in CDDP‐resistant cell models. This was associated with a significant decrease in cap‐dependent translation levels (P < 0.01). In vivo tumor xenografts data corroborated these results and confirmed that inhibition of AURKA was sufficient to overcome CDDP resistance in gastric cancer. Our data demonstrate that AURKA promotes acquired and de novo resistance to CDDP through regulation of p‐eIF4E (S209), c‐MYC, HDM2, and cap‐dependent translation. Targeting AURKA could be an effective therapeutic approach to overcome CDDP resistance in refractory gastric cancer and possibly other cancer types.
Collapse
Affiliation(s)
- Lihong Wang
- Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
| | - Janet Arras
- Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Ahmed Katsha
- Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Science and Engineering Department, Raritan Valley Community College, Branchburg, NJ, USA
| | - Saif Hamdan
- Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Abbes Belkhiri
- Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jeffrey Ecsedy
- Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge, MA, USA a wholly owned subsidiary of Takeda Pharmaceutical Company Limited
| | - Wael El-Rifai
- Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.,Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA
| |
Collapse
|
|
16
|
Riquelme I, Tapia O, Espinoza JA, Leal P, Buchegger K, Sandoval A, Bizama C, Araya JC, Peek RM, Roa JC. The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines. Pathol Oncol Res 2016; 22:797-805. [PMID: 27156070 DOI: 10.1007/s12253-016-0066-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 04/26/2016] [Indexed: 01/04/2023]
Abstract
The PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism and angiogenesis. Emerging evidence has shown that deregulation of this pathway has a role promoting gastric cancer (GC). The aim was to assess the expression of genes involved in this pathway by qPCR in 23 tumor and 23 non-tumor gastric mucosa samples from advanced GC patients, and in AGS, MKN28 and MKN45 gastric cancer cell lines. Results showed a slight overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1, EIF4EBP1 and EIF4E genes, and a slightly decreased PTEN and TSC1 expression. In AGS, MKN28 and MKN45 cells a significant gene overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1 and EIF4E, and a significant repression of PTEN gene expression were observed. Immunoblotting showed that PI3K-β, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E and p-eIF4E proteins were present in cell lines at different levels, confirming activation of this pathway in vitro. This is the first time this extensive panel of 9 genes within PI3K/AKT/mTOR pathway has been studied in GC to clarify the biological role of this pathway in GC and develop new strategies for this malignancy.
Collapse
Affiliation(s)
- Ismael Riquelme
- Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Avenida Alemania 0458, Postal Code, 4810296, Temuco, Chile.,Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Avenida Francisco Salazar 01145,Casilla 54-D, Temuco, Chile
| | - Oscar Tapia
- Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Avenida Alemania 0458, Postal Code, 4810296, Temuco, Chile
| | - Jaime A Espinoza
- Department of Pathology, Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile.,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Portugal 61, Postal Code, 8330034, Santiago, Chile.,Advanced Centre for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile
| | - Pamela Leal
- Molecular Biology and Biomedicine Lab, CEGIN-BIOREN, Universidad de La Frontera, Avenida Alemania 0458, Postal Code, 4810296, Temuco, Chile
| | - Kurt Buchegger
- Laboratory of Molecular Pathology, Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Avenida Alemania 0458, Postal Code, 4810296, Temuco, Chile.,Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Avenida Francisco Salazar 01145,Casilla 54-D, Temuco, Chile
| | - Alejandra Sandoval
- UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Portugal 61, Postal Code, 8330034, Santiago, Chile.,Advanced Centre for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile
| | - Carolina Bizama
- Department of Pathology, Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile.,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Portugal 61, Postal Code, 8330034, Santiago, Chile.,Advanced Centre for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile
| | - Juan Carlos Araya
- Department of Pathological Anatomy, School of Medicine, Universidad de La Frontera, Avenida Alemania 0458, Postal Code, 4810296, Temuco, Chile
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine and Cancer Biology, School of Medicine, Vanderbilt University, 2215 Garland Avenue Nashville, Postal Code, Nashville, TN, 37232, USA
| | - Juan Carlos Roa
- Department of Pathology, Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile. .,UC Centre for Investigational Oncology (CITO), School of Medicine, Pontificia Universidad Católica de Chile, Portugal 61, Postal Code, 8330034, Santiago, Chile. .,Advanced Centre for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, Marcoleta 377, 7th Floor, Postal Code, 8330024, Santiago, Chile.
| |
Collapse
|
|
17
|
Dahiya K, Dhankhar R. Updated overview of current biomarkers in head and neck carcinoma. World J Methodol 2016; 6:77-86. [PMID: 27018324 PMCID: PMC4804254 DOI: 10.5662/wjm.v6.i1.77] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 01/20/2016] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Squamous cell cancer is the most common type of malignancy arising from the epithelial cells of the head and neck region. Head and neck squamous cell carcinoma (HNSCC) is one of the predominant causes of cancer related casualties worldwide. Overall prognosis in this disease has improved to some extent with the advancements in therapeutic modalities but detection of primary tumor at its initial stage and prevention of relapse are the major targets to be achieved for further improvement in terms of survival rate of patients. Latest achievements in basic research regarding molecular characterization of the disease has helped in better perception of the molecular mechanisms involved in HNSCC progression and also in recognizing and targeting various molecular biomarkers associated with HNSCC. In the present article, we review the information regarding latest and potential biomarkers for the early detection of HNSCC. A detailed molecular characterization, ultimately, is likely to improve the development of new therapeutic strategies, potentially relevant to diagnosis and prognosis of head and neck cancers. The need for more accurate and timely disease prediction has generated enormous research interests in this field.
Collapse
|
|
18
|
Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis. Oncogene 2016; 35:4675-88. [DOI: 10.1038/onc.2015.515] [Citation(s) in RCA: 128] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 12/11/2015] [Accepted: 12/11/2015] [Indexed: 01/17/2023]
|
|
19
|
Thumma SC, Jacobson BA, Patel MR, Konicek BW, Franklin MJ, Jay-Dixon J, Sadiq A, De A, Graff JR, Kratzke RA. Antisense oligonucleotide targeting eukaryotic translation initiation factor 4E reduces growth and enhances chemosensitivity of non-small-cell lung cancer cells. Cancer Gene Ther 2015; 22:396-401. [PMID: 26227824 DOI: 10.1038/cgt.2015.34] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 06/30/2015] [Accepted: 07/10/2015] [Indexed: 12/12/2022]
Abstract
Elevated levels of eukaryotic translation initiation factor 4E (eIF4E) enhance translation of many malignancy-related proteins, such as vascular endothelial growth factor (VEGF), c-Myc and osteopontin. In non-small-cell lung cancer (NSCLC), levels of eIF4E are significantly increased compared with normal lung tissue. Here, we used an antisense oligonucleotide (ASO) to inhibit the expression of eIF4E in NSCLC cell lines. eIF4E levels were significantly reduced in a dose-dependent manner in NSCLC cells treated with eIF4E-specific ASO (4EASO) compared with control ASO. Treatment of NSCLC cells with the 4EASO resulted in decreased cap-dependent complex formation, decreased cell proliferation and increased sensitivity to gemcitabine. At the molecular level, repression of eIF4E with ASO resulted in decreased expression of the oncogenic proteins VEGF, c-Myc and osteopontin, whereas expression of β-actin was unaffected. Based on these findings, we conclude that eIF4E-silencing therapy alone or in conjunction with chemotherapy represents a promising approach deserving of further investigation in future NSCLC clinical trials.
Collapse
Affiliation(s)
- S C Thumma
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - B A Jacobson
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - M R Patel
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - B W Konicek
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - M J Franklin
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - J Jay-Dixon
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - A Sadiq
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - A De
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| | - J R Graff
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA
| | - R A Kratzke
- Division of Hematology, Department of Medicine, Oncology and Transplantation, University of Minnesota Medical School, Minneapolis, MN, USA
| |
Collapse
|
|
20
|
Abstract
Dysregulation of mRNA translation is a frequent feature of neoplasia. Many oncogenes and tumour suppressors affect the translation machinery, making aberrant translation a widespread characteristic of tumour cells, independent of the genetic make-up of the cancer. Therefore, therapeutic agents that target components of the protein synthesis apparatus hold promise as novel anticancer drugs that can overcome intra-tumour heterogeneity. In this Review, we discuss the role of translation in cancer, with a particular focus on the eIF4F (eukaryotic translation initiation factor 4F) complex, and provide an overview of recent efforts aiming to 'translate' these results to the clinic.
Collapse
|
|
21
|
Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3. Oncogene 2014; 34:2032-42. [PMID: 24909168 PMCID: PMC4978545 DOI: 10.1038/onc.2014.146] [Citation(s) in RCA: 205] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 03/17/2014] [Accepted: 03/19/2014] [Indexed: 02/08/2023]
Abstract
The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The mRNA cap-binding protein eIF4E is an oncoprotein that plays an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eIF4E cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that TGFβ induces eIF4E phosphorylation to promote translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFβ requires translational activation via the non-canonical TGFβ signaling branch acting through eIF4E phosphorylation.
Collapse
|
|
22
|
Tapia O, Riquelme I, Leal P, Sandoval A, Aedo S, Weber H, Letelier P, Bellolio E, Villaseca M, Garcia P, Roa JC. The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch 2014; 465:25-33. [PMID: 24844205 DOI: 10.1007/s00428-014-1588-4] [Citation(s) in RCA: 160] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 03/31/2014] [Accepted: 04/28/2014] [Indexed: 12/13/2022]
Abstract
Signaling pathway alterations are important in the development of gastric cancer (GC). Deregulation of the PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism, and angiogenesis. Our goal was to assess expression of proteins involved in the PI3K/AKT/mTOR pathway by immunohistochemistry (IHC) in tumor and nontumor gastric mucosa from patients with advanced GC. We evaluated 71 tumor and 71 nontumor gastric mucosa samples from advanced GC patients, selected from Hernán Henríquez Aravena Hospital (Temuco, Chile). The targets studied were PI3K, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E, and p-eIF4E. Expression data were correlated with clinicomorphological data. Descriptive and analytical statistics were used (95 % confidence interval, p < 0.05). For survival analyses, the Kaplan-Meier method and the log-rank test were used. PI3K, AKT, p-AKT, p-mTOR, p-4E-BP1, P70S6K1, p-P70S6K1, eIF-4E, and p-eIF-4E proteins were significantly overexpressed in tumor tissue. Conversely, PTEN was underexpressed in tumor tissue, notably in pT3-pT4 tumors (p = 0.02) and tumors with lymph node metastases (p < 0.001). P70S6K1 expression was associated with pT3-pT4 tumors (p = 0.03). Moreover, PI3K (p = 0.004), AKT (p = 0.01), p-AKT (p = 0.01), P70S6K1 (p = 0.04), p-P70S6K1 (p = 0.001), and eIF-4E (p = 0.004) were overexpressed in tumors with lymph node metastases. Low expression of 4E-BP1 was associated with poor overall survival (p = 0.03). Our results suggest that the PI3K/AKT/mTOR pathway is activated in GC, with overexpression in tumor tissue of most of the studied proteins (total and phosphorylated). These might be considered as target for specific targeted therapy in GC.
Collapse
Affiliation(s)
- Oscar Tapia
- Department of Pathology, Universidad de La Frontera, CEGIN-BIOREN, Temuco, Chile
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Singh J, Jayaraj R, Baxi S, Mileva M, Curtin J, Thomas M. An Australian retrospective study to evaluate the prognostic role of p53 and eIF4E cancer markers in patients with head and neck squamous cell carcinoma (HNSCC): study protocol. Asian Pac J Cancer Prev 2014; 14:4717-21. [PMID: 24083732 DOI: 10.7314/apjcp.2013.14.8.4717] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Complete surgical resection of the primary tumour is a crucial predictive step for head and neck squamous cell carcinoma (HNSCC), because incomplete resection may lead to increase in the recurrence rate. Molecular cancer markers have been investigated as potential predictors of prognosis marker, to identify patients who are at high risk of local recurrence. This retrospective study aimed to determine the prognostic correlation between p53 and eIF4E expression and clinical characteristics, recurrence and overall survival. Forty eight HNSCC patients were selected between 2006 and 2009 diagnosed at the Royal Darwin Hospital, Darwin, Northern Territory, Australia. Out of 48, only those 24 with negative surgical margins with hematoxylin and eosin (HandE) were chosen for further analysis. A total of 77 surgical margins were obtained and subsequently analysed by immunohistochemical (IHC) staining with monoclonal p53 and polyclonal eIF4E antibodies. Contingency table and χ2-test were used to investigate the correlation between p53 and eIF4E expression and clinical characteristics, recurrence and overall survival of the HNSCC patients. The follow up period was 74 months (range 1-74 months). The Kaplan-Meier method was used to generate recurrence and survival curves. This is a first retrospective study of Northern Territory patients, including Indigenous and non-Indigenous Australians. Molecular study of surgical margins could help to identify patients with and without clear margins after surgery and help in choice of the most appropriate adjuvant treatment for HNSCC patients.
Collapse
Affiliation(s)
- Jagtar Singh
- School of Psychological and Clinical Sciences, Charles Darwin University, Darwin, Northern Territory, Australia E-mail :
| | | | | | | | | | | |
Collapse
|
|
24
|
Small-molecule inhibition of oncogenic eukaryotic protein translation in mesothelioma cells. Invest New Drugs 2014; 32:598-603. [DOI: 10.1007/s10637-014-0076-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 02/18/2014] [Indexed: 02/01/2023]
|
|
25
|
Jacobson BA, Thumma SC, Jay-Dixon J, Patel MR, Dubear Kroening K, Kratzke MG, Etchison RG, Konicek BW, Graff JR, Kratzke RA. Targeting eukaryotic translation in mesothelioma cells with an eIF4E-specific antisense oligonucleotide. PLoS One 2013; 8:e81669. [PMID: 24260583 PMCID: PMC3832430 DOI: 10.1371/journal.pone.0081669] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 10/17/2013] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Aberrant cap-dependent translation is implicated in tumorigenesis in multiple tumor types including mesothelioma. In this study, disabling the eIF4F complex by targeting eIF4E with eIF4E-specific antisense oligonucleotide (4EASO) is assessed as a therapy for mesothelioma. METHODS Mesothelioma cells were transfected with 4EASO, designed to target eIF4E mRNA, or mismatch-ASO control. Cell survival was measured in mesothelioma treated with 4EASO alone or combined with either gemcitabine or pemetrexed. Levels of eIF4E, ODC, Bcl-2 and β-actin were assessed following treatment. Binding to a synthetic cap-analogue was used to study the strength of eIF4F complex activation following treatment. RESULTS eIF4E level and the formation of eIF4F cap-complex decreased in response to 4EASO, but not mismatch control ASO, resulting in cleavage of PARP indicating apoptosis. 4EASO treatment resulted in dose dependent decrease in eIF4E levels, which corresponded to cytotoxicity of mesothelioma cells. 4EASO resulted in decreased levels of eIF4E in non-malignant LP9 cells, but this did not correspond to increased cytotoxicity. Proteins thought to be regulated by cap-dependent translation, Bcl-2 and ODC, were decreased upon treatment with 4EASO. Combination therapy of 4EASO with pemetrexed or gemcitabine further reduced cell number. CONCLUSION 4EASO is a novel drug that causes apoptosis and selectively reduces eIF4E levels, eIF4F complex formation, and proliferation of mesothelioma cells. eIF4E knockdown results in decreased expression of anti-apoptotic and pro-growth proteins and enhances chemosensitivity.
Collapse
Affiliation(s)
- Blake A. Jacobson
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Saritha C. Thumma
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Joseph Jay-Dixon
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Manish R. Patel
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - K. Dubear Kroening
- Department of Biological Sciences, University of Wisconsin-Fox Valley, Menasha, Wisconsin, United States of America
| | - Marian G. Kratzke
- Research Service, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota, United States of America
| | - Ryan G. Etchison
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Bruce W. Konicek
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Jeremy R. Graff
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Robert A. Kratzke
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
- * E-mail:
| |
Collapse
|
|
26
|
Liang S, Guo R, Zhang Z, Liu D, Xu H, Xu Z, Wang X, Yang L. Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth. Oncol Rep 2013; 29:2422-30. [PMID: 23588929 DOI: 10.3892/or.2013.2397] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 03/15/2013] [Indexed: 12/16/2022] Open
Abstract
The increase of eukaryotic translation initiation factor 4E (eIF4E) expression is frequently observed in several types of cancer, making eIF4E an attractive anticancer drug target. However, the role of eIF4E in gastric cancer pathogenesis remains unclear. Perifosine is a bioavailable alkylphospholipid exhibiting antitumor activity in a series of cancer types. In this study, gastric cancer cell lines were selected to explore the role of eIF4E as a potential target for treating human gastric cancer. The expression of total eIF4E (T-eIF4E)and phosphorylated eIF4E (p-eIF4E) in gastric cancer samples was detected by immunohistochemical assay. RNA interference was used to silence eIF4E expression. Sulforhodamine B assay was performed to evaluate tumor cell viability. Colony formation assay was used to examine the effects of eIF4E small interfering RNA (siRNA) or perifosine on colony formation. The mRNA levels of eIF4E were analyzed by qRT-PCR and western blot analysis was carried out to evaluate the expression of Akt and eIF4E. The results showed that increased expression levels of T-eIF4E and p-eIF4E were found in gastric cancer tissues and cells. Reduced eIF4E expression blocked the proliferation of gastric cancer cells. Perifosine downregulated the T-eIF4E and p-eIF4E levels in a dose- and time-dependent manner; it also inhibited the growth of gastric cancer cells. Moreover, this inhibitory effect was significantly enhanced by the combination of eIF4E siRNA and perifosine treatments. Our results indicate that eIF4E gene silencing can inhibit tumor cell growth, and eIF4E can be developed as a promising therapeutic target for gastric cancer.
Collapse
Affiliation(s)
- Song Liang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | | | | | | | | | | | | | | |
Collapse
|
|
27
|
EIF4E over-expresses and enhances cell proliferation and cell cycle progression in nasopharyngeal carcinoma. Med Oncol 2013; 30:400. [PMID: 23277284 DOI: 10.1007/s12032-012-0400-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 10/05/2012] [Indexed: 12/13/2022]
Abstract
Eukaryotic translation initiation factor 4E (eIF4E) is involved in integration and amplification of many carcinogenesis signals in tumors. However, it remains unclear whether eIF4E over-expresses in NPC and whether it is associated with the development of NPC. Here, we analyzed the expression state of eIF4E, c-Myc, and MMP9 in 24 nasopharyngitises and 64 nasopharyngeal carcinomas (NPC) tissues and studied the influences of eIF4E on the proliferation and cell cycle in NPC cell lines. The results indicate that eIF4E might over-express in NPC and the over-expression of eIF4E promotes NPC growth and cell cycle progression through enhancing the translational expression of c-Myc and MMP9. The finding certainly adds new knowledge in the understanding of the carcinogenesis of NPC and provides a potential molecular target for the NPC therapy and prevention.
Collapse
|
|
28
|
Labisso WL, Wirth M, Stojanovic N, Stauber RH, Schnieke A, Schmid RM, Krämer OH, Saur D, Schneider G. MYC directs transcription of MCL1 and eIF4E genes to control sensitivity of gastric cancer cells toward HDAC inhibitors. Cell Cycle 2012; 11:1593-602. [PMID: 22456335 DOI: 10.4161/cc.20008] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Histone deacetylases (HDACs) control fundamental physiological processes such as proliferation and differentiation. HDAC inhibitors (HDACi) induce cell cycle arrest and apoptosis of tumor cells. Therefore, they represent promising cancer therapeutics that appear particularly useful in combination therapies. Although HDACi are tested in current clinical trials, the molecular mechanisms modulating the cellular responses toward HDACi are incompletely understood. To gain insight into pathways that limit HDACi efficacy in gastric cancer, we treated a panel of gastric cancer cells with the clinically relevant HDACi suberoylanilide hydroxamic acid (SAHA). We report that higher expression levels of the anti-apoptotic BCL2 family members MCL1 and BCL(XL) were detectable in cells with high inhibitory concentration 50 (IC(50)) values for SAHA. Using RNAi, we show that MCL1 and BCL(XL) lower the efficacy of SAHA. To find strategies to interfere with MCL1 and BCL(XL) expression, we investigated molecular regulation of both proteins. We show that specific siRNAs against c-MYC as well as pharmacological inhibition of this cancer-relevant transcription factor reduced MCL1 and BCL(XL) expression. Subsequently, we observed an increase in SAHA efficacy. Our data furthermore demonstrate that two different molecular mechanisms are responsible for the modulation of these factors. Whereas c-MYC controls transcription of MCL1 directly, regulation of BCL(XL) was due to c-MYC's capability to regulate the eIF4E gene, which encodes a rate-limiting factor of eukaryotic translation. Our data reveal a new molecular mechanism for how c-MYC controls cell autonomous apoptosis and provide a rationale for a concerted inhibition of HDACs and c-MYC in gastric cancer.
Collapse
Affiliation(s)
- Wajana L Labisso
- II Medizinische Klinik, Technische Universität München, München, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Hayman TJ, Williams ES, Jamal M, Shankavaram UT, Camphausen K, Tofilon PJ. Translation initiation factor eIF4E is a target for tumor cell radiosensitization. Cancer Res 2012; 72:2362-72. [PMID: 22397984 DOI: 10.1158/0008-5472.can-12-0329] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
A core component in the cellular response to radiation occurs at the level of translational control of gene expression. Because a critical element in translation control is the availability of the initiation factor eIF4E, which selectively enhances the cap-dependent translation of mRNAs, we investigated a regulatory role for eIF4E in cellular radiosensitivity. eIF4E silencing enhanced the radiosensitivity of tumor cell lines but not normal cells. Similarly, pharmacologic inhibition of eIF4E with ribavirin also enhanced tumor cell radiosensitivity. eIF4E attenuation did not affect cell-cycle phase distribution or radiation-induced apoptosis, but it delayed the dispersion of radiation-induced γH2AX foci and increased the frequency of radiation-induced mitotic catastrophe. Radiation did not affect 4E-BP1 phosphorylation or cap-complex formation but it increased eIF4E binding to more than 1,000 unique transcripts including many implicated in DNA replication, recombination, and repair. Taken together, our findings suggest that eIF4E represents a logical therapeutic target to increase tumor cell radiosensitivity.
Collapse
Affiliation(s)
- Thomas J Hayman
- University of South Florida Morsani College of Medicine, Tampa, Florida, USA
| | | | | | | | | | | |
Collapse
|
|
30
|
Translational control gone awry: a new mechanism of tumorigenesis and novel targets of cancer treatments. Biosci Rep 2011; 31:1-15. [PMID: 20964625 DOI: 10.1042/bsr20100077] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Translational control is one of primary regulation mechanisms of gene expression. Eukaryotic translational control mainly occurs at the initiation step, the speed-limiting step, which involves more than ten translation initiation factors [eIFs (eukaryotic initiation factors)]. Changing the level or function of these eIFs results in abnormal translation of specific mRNAs and consequently abnormal growth of cells that leads to human diseases, including cancer. Accumulating evidence from recent studies showed that the expression of many eIFs was associated with malignant transformation, cancer prognosis, as well as gene expression regulation. In the present paper, we perform a critical review of recent advances in understanding the role and mechanism of eIF action in translational control and cancer as well as the possibility of targeting eIFs for therapeutic development.
Collapse
|
|
31
|
Borden KLB, Culjkovic-Kraljacic B. Ribavirin as an anti-cancer therapy: acute myeloid leukemia and beyond? Leuk Lymphoma 2011; 51:1805-15. [PMID: 20629523 DOI: 10.3109/10428194.2010.496506] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Ribavirin was discovered nearly 40 years ago as a broad-spectrum antiviral drug. Recent data suggest that ribavirin may also be an effective cancer therapy. In this case, ribavirin targets an oncogene, the eukaryotic translation initiation factor eIF4E, elevated in approximately 30% of cancers including many leukemias and lymphomas. Specifically, ribavirin impedes eIF4E mediated oncogenic transformation by acting as an inhibitor of eIF4E. In a phase II clinical trial, ribavirin treatment led to substantial clinical benefit in patients with poor-prognosis acute myeloid leukemia (AML). Here molecular targeting of eIF4E correlated with clinical response. Ribavirin also targets a key enzyme in the guanosine biosynthetic pathway, inosine monophosphate dehydrogenase (IMPDH), and also modulates immunity. Parallels with known antiviral mechanisms could be informative; however, after 40 years, these are not entirely clear. The antiviral effects of ribavirin appear cell-type specific. This variation likely arises for many reasons, including cell specific variations in ribavirin metabolism as well as virus specific factors. Thus, it seems that the mechanisms for ribavirin action in cancer therapy may also vary in terms of the cancer/tissue under study. Here we review the anticancer activities of ribavirin and discuss the possible utility of incorporating ribavirin into diverse cancer therapeutic regimens.
Collapse
Affiliation(s)
- Katherine L B Borden
- Institute of Research in Immunology and Cancer (IRIC), Department of Pathology and Cell Biology, Université de Montréal, Montreal, QC, Canada.
| | | |
Collapse
|
|
32
|
Hsu HS, Chen HW, Kao CL, Wu ML, Li AFY, Cheng TH. MDM2 is overexpressed and regulated by the eukaryotic translation initiation factor 4E (eIF4E) in human squamous cell carcinoma of esophagus. Ann Surg Oncol 2010; 18:1469-77. [PMID: 21080085 DOI: 10.1245/s10434-010-1428-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Indexed: 11/18/2022]
Abstract
BACKGROUND We investigated the association between the increased eukaryotic translation initiation factor 4E (eIF4E) level and MDM2 overexpression in the esophageal cancer tissue and cells. METHODS This was a retrospective study of specimens from esophageal cancer patients treated over a 5-year period in a Taiwan university hospital. The predictor variable was eIF4E level in esophageal tumors and CE48T/VGH and TE6 esophageal carcinoma cell lines. The main outcome variable was MDM2 overexpression. Appropriate descriptive and univariate statistics were computed, and a P value of <0.05 was considered statistically significant. RESULTS There were two study sample groups. Immunohistochemistry analyses of the first sample group (51 esophageal tumors) revealed that 19 specimens demonstrated MDM2 elevation and 20 specimens had eIF4E overexpression. eIF4E elevation was evidenced by accumulation of the protein in the cytoplasm. There was a significant association between the eIF4E and MDM2 expression (P < 0.001). Western blot analysis and semiquantitative reverse transcriptase-polymerase chain reaction of the second specimen group (20 pairs of tumors and normal tissues) revealed the co-elevation of MDM2 and eIF4E (P = 0.008). There was no increased mdm2 transcript in most of the specimens. Without significant alterations in the mdm2 mRNA level and subcellular distribution, MDM2 protein was upregulated in CE48T/VGH cultured cells expressing ectopic eIF4E. Conversely, reduction of eIF4E by specific siRNA enabled TE6 cells synthesizing reduced amounts of MDM2. CONCLUSIONS Our findings indicate that MDM2 protein levels are strongly associated with and regulated by eIF4E in a posttranscriptional mechanism in esophageal cancer.
Collapse
Affiliation(s)
- Han-Shui Hsu
- National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
| | | | | | | | | | | |
Collapse
|
|
33
|
Dumstorf CA, Konicek BW, McNulty AM, Parsons SH, Furic L, Sonenberg N, Graff JR. Modulation of 4E-BP1 Function as a Critical Determinant of Enzastaurin-Induced Apoptosis. Mol Cancer Ther 2010; 9:3158-63. [DOI: 10.1158/1535-7163.mct-10-0413] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
34
|
Hsieh AC, Ruggero D. Targeting eukaryotic translation initiation factor 4E (eIF4E) in cancer. Clin Cancer Res 2010; 16:4914-20. [PMID: 20702611 DOI: 10.1158/1078-0432.ccr-10-0433] [Citation(s) in RCA: 145] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recent advances in understanding the role of eukaryotic translation initiator factor 4E (eIF4E) in tumorigenesis and cancer progression have generated significant interest in therapeutic agents that indirectly or directly target aberrant activation of eIF4E in cancer. Here, we address the general function of eIF4E in translation initiation and cancer, present evidence supporting its role in cancer initiation and progression, and highlight emerging therapeutics that efficiently target hyperactivated eIF4E. In doing so, we also highlight the major differences between these therapeutics that may influence their mechanism of action.
Collapse
Affiliation(s)
- Andrew C Hsieh
- Department of Urology, Helen Diller Family Comprehensive Cancer Center, School of Medicine, University of California, San Francisco, San Francisco, California, USA
| | | |
Collapse
|
|
35
|
Inamdar KV, Romaguera JE, Drakos E, Knoblock RJ, Garcia M, Leventaki V, Medeiros LJ, Rassidakis GZ. Expression of eukaryotic initiation factor 4E predicts clinical outcome in patients with mantle cell lymphoma treated with hyper-CVAD and rituximab, alternating with rituximab, high-dose methotrexate, and cytarabine. Cancer 2009; 115:4727-36. [PMID: 19708031 DOI: 10.1002/cncr.24506] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Oncogenic AKT/mammalian target of rapamycin (mTOR) signaling has recently been shown to contribute to tumor survival and proliferation in mantle cell lymphoma (MCL) through its downstream effector eukaryotic initiation factor 4E (eIF4E), which may control cyclin D1 protein levels. However, the clinical significance of eIF4E expression in MCL is unknown. METHODS The authors investigated the prognostic significance of eIF4E expression in 70 MCL patients uniformly treated with hyper-CVAD and rituximab, alternating with the rituximab, high-dose methotrexate, and cytarabine regimen (R-hyper-CVAD). eIF4E expression was assessed using tissue biopsy specimens obtained before treatment, immunohistochemical methods, and a highly specific monoclonal antibody. Failure-free (FFS) and overall (OS) survival were used as endpoints in univariate and multivariate survival analysis. RESULTS High eIF4E expression was found in 28 (40%) MCL tumors. After a median follow-up of 51 months for survivors, the 5-year FFS was 20.6% for patients with high eIF4E expression, compared with 63.5% for patients with low or no eIF4E expression (P=.01, log-rank). Similarly, the 5-year OS was 40.1% for patients with high eIF4E expression, compared with 73.8% for patients with low or no eIF4E expression (P=.018, log-rank). In multivariate analysis, eIF4E expression was associated with poorer FFS and OS, along with age>60 years and high beta2-microglobulin in the final prognostic model. CONCLUSIONS In summary, eIF4E, which seems to recapitulate most of the biologic effects of mTOR signaling in MCL, is an independent predictor of clinical outcome in MCL patients uniformly treated with the R-hyper-CVAD regimen.
Collapse
Affiliation(s)
- Kedar V Inamdar
- Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat 2008; 11:63-76. [PMID: 18440854 PMCID: PMC2519122 DOI: 10.1016/j.drup.2008.03.001] [Citation(s) in RCA: 198] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2008] [Revised: 03/12/2008] [Accepted: 03/14/2008] [Indexed: 02/06/2023]
Abstract
The mammalian target of rapamycin (mTOR) pathway plays a central role in regulating protein synthesis, ribosomal protein translation, and cap-dependent translation. Deregulations in mTOR signaling are frequently associated with tumorigenesis, angiogenesis, tumor growth and metastasis. This review highlights the role of the mTOR in anticancer drug resistance. We discuss the network of signaling pathways in which the mTOR kinase is involved, including the structure and activation of the mTOR complex and the pathways upstream and downstream of mTOR as well as other molecular interactions of mTOR. Major upstream signaling components in control of mTOR activity are PI3K/PTEN/AKT and Ras/Raf/MEK/ERK pathways. We discuss the central role of mTOR in mediating the translation of mRNAs of proteins related to cell cycle progression, those involved in cell survival such as c-myc, hypoxia inducible factor 1* (HIF-1*) and vascular endothelial growth factor (VEGF), cyclin A, cyclin dependent kinases (cdk1/2), cdk inhibitors (p21(Cip1) and p27(Kip1)), retinoblastoma (Rb) protein, and RNA polymerases I and III. We then discuss the potential therapeutic opportunities for using mTOR inhibitors rapamycin, CCI-779, RAD001, and AP-23573 in cancer therapy as single agents or in combinations to reverse drug resistance.
Collapse
Affiliation(s)
- Bing-Hua Jiang
- Department of Microbiology, Mary Babb Randolph Cancer Center, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA.
| | | |
Collapse
|
|
37
|
Phosphorylation of ribosomal p70 S6 kinase and rapamycin sensitivity in human colorectal cancer. Cancer Lett 2007; 251:105-13. [DOI: 10.1016/j.canlet.2006.11.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2006] [Revised: 11/03/2006] [Accepted: 11/07/2006] [Indexed: 01/02/2023]
|
|
38
|
Bilanges B, Stokoe D. Mechanisms of translational deregulation in human tumors and therapeutic intervention strategies. Oncogene 2007; 26:5973-90. [PMID: 17404576 DOI: 10.1038/sj.onc.1210431] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Analysis of the recurrent genetic aberrations present in human tumors provides insight into how normal cells escape appropriate proliferation and survival cues. Commonly mutated genes encode proteins that monitor DNA damage (e.g., p53), proteins that regulate the cell cycle (such as Rb), and proteins that regulate signal transduction pathways (such as APC, PTEN and Ras). Analysis of the relevant targets and downstream events of these genes in normal and tumor cells will clearly highlight important pathways for tumorigenesis. However, more infrequent mutations are also informative in defining events critical for the process of tumorigenesis, and often delineate important pathways lying downstream of commonly mutated oncogenes and tumor suppressors. Together, these studies have led to the conclusion that deregulated protein synthesis plays an important role in human cancer. This review will discuss the evidence implicating mRNA translation as an important downstream consequence of signal transduction pathways initiated by mutated oncogenes and tumor suppressors, as well as additional genetic findings implicating the importance of global and specific translational control in human cancer. It will also discuss therapeutic strategies that take advantage of differences in translational regulation between normal and tumor cells.
Collapse
Affiliation(s)
- B Bilanges
- UCSF Cancer Research Institute, San Francisco, CA 94115, USA.
| | | |
Collapse
|