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Boghean L, Singh S, Mangalaparthi KK, Kizhake S, Umeta L, Wishka D, Grothaus P, Pandey A, Natarajan A. A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network. Molecules 2025; 30:2001. [PMID: 40363807 PMCID: PMC12073402 DOI: 10.3390/molecules30092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
The quinoxaline core is found in several biologically active compounds, with Erdafitinib being the first FDA-approved quinoxaline derivative that targets a kinase and exhibits anti-cancer properties. We previously reported a quinoxaline analog (84) that displayed anti-cancer effects by inhibiting IKKβ, a key kinase in the NFκB pathway. Here, we present the synthesis of a regioisomer (51-106) and its characterization as a selective MAP3K1 inhibitor with improved metabolic stability and oral bioavailability. We used the small molecule MAP3K1 inhibitor in a proteomics study that identified NPM1 as a member of the MAP3K1 network.
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Affiliation(s)
- Lidia Boghean
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Sarbjit Singh
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kiran K. Mangalaparthi
- Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; (K.K.M.); (A.P.)
| | - Smitha Kizhake
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Lelisse Umeta
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Donn Wishka
- Drug Synthesis and Chemistry Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA (P.G.)
| | - Paul Grothaus
- Drug Synthesis and Chemistry Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA (P.G.)
| | - Akhilesh Pandey
- Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; (K.K.M.); (A.P.)
- Department of Community Medicine, Manipal Academy of Higher Education, Manipal 576104, India
| | - Amarnath Natarajan
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Weidle UH, Birzele F. Prostate Cancer: De-regulated Circular RNAs With Efficacy in Preclinical In Vivo Models. Cancer Genomics Proteomics 2025; 22:136-165. [PMID: 39993805 PMCID: PMC11880926 DOI: 10.21873/cgp.20494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 11/28/2025] [Accepted: 12/03/2024] [Indexed: 02/26/2025] Open
Abstract
Therapy resistance, including castration-resistance and metastasis, remains a major hurdle in the treatment of prostate cancer. In order to identify novel therapeutic targets and treatment modalities for prostate cancer, we conducted a comprehensive literature search on PubMed to identify de-regulated circular RNAs that influence treatment efficacy in preclinical prostate cancer-related in vivo models. Our analysis identified 49 circular RNAs associated with various processes, including treatment resistance, transmembrane and secreted proteins, transcription factors, signaling cascades, human antigen R, nuclear receptor binding, ubiquitination, metabolism, epigenetics and other target categories. The identified targets and circular RNAs can be further scrutinized through target validation approaches. Down-regulated circular RNAs are candidates for reconstitution therapy, while up-regulated RNAs can be inhibited using small interfering RNA (siRNA), antisense oligonucleotides (ASO) or clustered regularly interspaced short palindromic repeats/CRISPR associated (CRISPR-CAS)-related approaches.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
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Cai YW, Liu CC, Zhang YW, Liu YM, Chen L, Xiong X, Shao ZM, Yu KD. MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer. J Clin Invest 2024; 135:e183656. [PMID: 39531335 PMCID: PMC11735090 DOI: 10.1172/jci183656] [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: 06/05/2024] [Accepted: 11/01/2024] [Indexed: 11/16/2024] Open
Abstract
Treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, the most common type of breast cancer, has faced challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of patients with HR+/HER2- breast cancer (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to mitogen-activated protein kinase kinase kinase 1 (MAP3K1) mutation and we validated experimentally that a MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNA, thereby driving tumor immune escape. In preclinical models, the postbiotic tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as what we believe to be a novel therapeutic strategy to enhance the efficacy of immunotherapy.
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Affiliation(s)
- Yu-Wen Cai
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
| | - Cui-Cui Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
| | - Yan-Wu Zhang
- Department of Breast Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi-Ming Liu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
| | - Lie Chen
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
| | - Xin Xiong
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
| | - Zhi-Ming Shao
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
| | - Ke-Da Yu
- Department of Breast Surgery, Fudan University Shanghai Cancer Center and Cancer Institute, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Key Laboratory of Breast Cancer in Shanghai, Shanghai, China
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Wu S, Xue S, Tang Y, Zhao W, Zheng M, Cheng Z, Hu X, Sun J, Ren J. Mitogen-activated protein kinase kinase kinase 1 facilitates the temozolomide resistance and migration of GBM via the MEK/ERK signalling. J Cell Mol Med 2024; 28:e70173. [PMID: 39443331 PMCID: PMC11499072 DOI: 10.1111/jcmm.70173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 10/01/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024] Open
Abstract
Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) is overexpressed in gliomas; however, its clinical significance, biological functions, and underlying molecular mechanisms remain unclear. Abnormal overexpression of MAP3K1 in glioma is strongly associated with unfavourable clinicopathological characteristics and disease progression. MAP3K1 could potentially serve as a reliable diagnostic and prognostic biomarker for glioma. MAP3K1 silencing suppressed the migration but had no effect on the proliferation and cell death of Glioblastoma Multiforme (GBM) cells. MAP3K1 knockdown exacerbated the temozolomide (TMZ) induced inhibition of glioma cell proliferation and death of GBM cells. In addition, MAP3K1 knockdown combined with TMZ treatment significantly inhibited the growth and increased cell death in organoids derived from GBM patients. MAP3K1 knockdown reversed TMZ resistance of GBM in intracranial glioma model. In terms of molecular mechanisms, the phosphorylation level of ERK was significantly decreased by MAP3K1 silencing. No significant change in the JNK pathway was found in MAP3K1-silenced GBM cells. Inhibition of ERK phosphorylation suppressed the migration and enhanced the TMZ sensibility of GBM cells. MAP3K1 was correlated with the immune infiltration in glioma. MAP3K1 could facilitate the migration and TMZ resistance of GBM cells through MEK/ERK signalling.
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Affiliation(s)
- Sicheng Wu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Senrui Xue
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Yuchen Tang
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
- School of Life SciencesXuzhou Medical UniversityXuzhouJiangsuChina
| | - Wenyu Zhao
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
- Laboratory of Clinical and Experimental Pathology, Department of PathologyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Maojin Zheng
- Laboratory of Clinical and Experimental Pathology, Department of PathologyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Zhixuan Cheng
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
- School of Life SciencesXuzhou Medical UniversityXuzhouJiangsuChina
| | - Xin Hu
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
- School of Life SciencesXuzhou Medical UniversityXuzhouJiangsuChina
| | - Jinmin Sun
- Laboratory of Clinical and Experimental Pathology, Department of PathologyXuzhou Medical UniversityXuzhouJiangsuChina
| | - Jing Ren
- Jiangsu Key Laboratory of Brain Disease Bioinformation, Research Center for Biochemistry and Molecular BiologyXuzhou Medical UniversityXuzhouJiangsuChina
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Kuo SH, Wei MF, Lee YH, Lin JC, Yang WC, Yang SY, Huang CS. MAP3K1 expression is associated with progression and poor prognosis of hormone receptor-positive, HER2-negative early-stage breast cancer. Cell Oncol (Dordr) 2023; 46:1213-1234. [PMID: 37166744 DOI: 10.1007/s13402-023-00805-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2023] [Indexed: 05/12/2023] Open
Abstract
PURPOSE In this study, we assessed whether the overexpression of MAP3K1 promotes the proliferation, migration, and invasion of breast cancer cells, which affect the prognosis of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early stage breast cancer. METHODS Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D) overexpressing MAP3K1 were transfected with two MAP3K1 short hairpin RNA plasmids (shMAP3K1 [#3] and shMAP3K1 [#5]). The proliferation, migration, and invasion of these cells were then examined. We assessed whether shMAP3K1 affects the cell cycle, levels of downstream signaling molecules (ERK, JNK, p38 MAPK, and NF-κB), and sensitivity to chemotherapeutic and hormonal agents. To assess the anti-tumor effect of MAP3K1 knockdown in the breast cancer orthotopic model, MCF7 and T-47D cells treated with or without shMAP3K1 (#3) and shMAP3K1 (#5) were inoculated into the mammary fat pads of mice. In total, 182 patients with HR-positive, HER2-negative T1 and T2 breast cancer and 0-3 nodal metastases were included. Additionally, 73 patients with T1 and T2 breast cancer and negative nodes who received adjuvant endocrine therapy alone were selected as an independent validation cohort. RESULTS In both cell lines, shMAP3K1 (#3) and shMAP3K1 (#5) significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and by blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Moreover, both shMAP3K1 (#3) and shMAP3K1 (#5) downregulated ERK-, JNK-, p38 MAPK-, and NF-κB-dependent gene transcription and enhanced the sensitivity of both cell lines to doxorubicin, docetaxel, and tamoxifen. We observed that both shMAP3K1 (#3) and shMAP3K1 (#5) inhibited tumor growth compared with that in the scrambled group of MCF7 and T-47D cell orthotopic tumors. Patients with MAP3K1 overexpression exhibited significantly poorer 10-year disease-free survival (DFS) (70.4% vs. 88.6%, p = 0.003) and overall survival (OS) (81.9% vs. 96.3%, p = 0.001) than those without MAP3K1 overexpression. Furthermore, phospho-ERK (p < 0.001) and phospho-JNK (p < 0.001) expressions were significantly associated with MAP3K1 expression, and both phospho-ERK and phospho-JNK expressions were significantly correlated with poor 10-year DFS and OS. These biological findings, including a significant association between DFS and OS, and the expressions of MAP3K1, phospho-ERK, and phospho-JNK were further validated in an independent cohort. Multivariate analysis identified MAP3K1 expression as an independent poor prognostic factor for DFS and OS. CONCLUSION Our results indicate that the overexpression of MAP3K1 plays a major role in the poor prognosis of HR-positive, HER2-negative early stage breast cancer.
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Affiliation(s)
- Sung-Hsin Kuo
- Departments of Oncology, National Taiwan University Hospital , Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Feng Wei
- Departments of Oncology, National Taiwan University Hospital , Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Hsuan Lee
- Departments of Pathology, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jui-Chueh Lin
- Departments of Oncology, National Taiwan University Hospital , Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Chi Yang
- Departments of Oncology, National Taiwan University Hospital , Taipei, Taiwan
- Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shi-Yi Yang
- Department of Surgery, National Taiwan University Hospital, and College of Medicine, National Taiwan University, No. 7, Chung-Shan South Rd, Taipei, Taiwan
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chiun-Sheng Huang
- Department of Surgery, National Taiwan University Hospital, and College of Medicine, National Taiwan University, No. 7, Chung-Shan South Rd, Taipei, Taiwan.
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Napoleon JV, Sagar S, Kubica SP, Boghean L, Kour S, King HM, Sonawane YA, Crawford AJ, Gautam N, Kizhake S, Bialk PA, Kmiec E, Mallareddy JR, Patil PP, Rana S, Singh S, Prahlad J, Grandgenett PM, Borgstahl GEO, Ghosal G, Alnouti Y, Hollingsworth MA, Radhakrishnan P, Natarajan A. Small-molecule IKKβ activation modulator (IKAM) targets MAP3K1 and inhibits pancreatic tumor growth. Proc Natl Acad Sci U S A 2022; 119:e2115071119. [PMID: 35476515 PMCID: PMC9170026 DOI: 10.1073/pnas.2115071119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 03/29/2022] [Indexed: 11/18/2022] Open
Abstract
Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKβ and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKβ is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKβ in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKβ inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKβ but inhibited the IKKβ kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKβ phosphorylation was inhibited by 39-100, thus we termed it IKKβ activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKβ levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKβ activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway.
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Affiliation(s)
- John Victor Napoleon
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Satish Sagar
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Sydney P. Kubica
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Lidia Boghean
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Smit Kour
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Hannah M. King
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Yogesh A. Sonawane
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Ayrianne J. Crawford
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Nagsen Gautam
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198
| | - Smitha Kizhake
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Pawel A. Bialk
- Gene Editing Institute, Christiana Care, Newark, DE 19713
| | - Eric Kmiec
- Gene Editing Institute, Christiana Care, Newark, DE 19713
| | | | - Prathamesh P. Patil
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Sandeep Rana
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Sarbjit Singh
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Janani Prahlad
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Paul M. Grandgenett
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Gloria E. O. Borgstahl
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
| | - Gargi Ghosal
- Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198
| | - Yazen Alnouti
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198
| | - Michael A. Hollingsworth
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198
| | - Prakash Radhakrishnan
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198
| | - Amarnath Natarajan
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198
- Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198
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Park HB, Baek KH. E3 ligases and deubiquitinating enzymes regulating the MAPK signaling pathway in cancers. Biochim Biophys Acta Rev Cancer 2022; 1877:188736. [DOI: 10.1016/j.bbcan.2022.188736] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/30/2022] [Accepted: 05/11/2022] [Indexed: 12/13/2022]
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Traub B, Roth A, Kornmann M, Knippschild U, Bischof J. Stress-activated kinases as therapeutic targets in pancreatic cancer. World J Gastroenterol 2021; 27:4963-4984. [PMID: 34497429 PMCID: PMC8384741 DOI: 10.3748/wjg.v27.i30.4963] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/17/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
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Affiliation(s)
- Benno Traub
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Aileen Roth
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Marko Kornmann
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
| | - Joachim Bischof
- Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany
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Zong M, Feng W, Wan L, Yu X, Yu W. miR-203 affects esophageal cancer cell proliferation, apoptosis and invasion by targeting MAP3K1. Oncol Lett 2020; 20:751-757. [PMID: 32566001 PMCID: PMC7285942 DOI: 10.3892/ol.2020.11610] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 01/24/2020] [Indexed: 12/13/2022] Open
Abstract
miR-203 has been indicated to be a tumor suppressor in esophageal cancer, however, the underlying molecular mechanisms by which it functions are not fully understood. The present study aimed to investigate the molecular mechanisms underlying the regulatory activities of microRNA (miR)-203 in esophageal cancer. The miR-203 mimic/inhibitor, Mitogen-Activated Protein Kinase Kinase Kinase 1 (MAP3K1) overexpression plasmid and MAP3K1 small interfering (si)RNA were transfected into TE-1 cells. miR-203 and MAP3K1 mRNA expression were detected via reverse transcription-quantitative PCR analysis, while MAP3K1 protein expression was detected via western blot analysis. Dual-luciferase reporter assay was used to determine whether MAP3K1 was a direct target of miR-203. Cell proliferation and invasion abilities were assessed via MTT and Matrigel assays, respectively. Cell apoptosis was analyzed via flow cytometry, Caspase 8/3 Assay kits and western blot analysis. The results demonstrated that MAP3K1 was a direct target of miR-203. Overexpression of MAP3K1 reversed the suppressed cell proliferation and invasion abilities induced by miR-203 mimic, as well as the inhibitory effect of miR-203 mimic on cell apoptosis. Furthermore, MAP3K1 siRNA weakened the effect of miR-203 inhibitor on cell proliferation, apoptosis and invasion.
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Affiliation(s)
- Mingzhu Zong
- Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Wanting Feng
- Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Li Wan
- Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Xiaojuan Yu
- Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Weiyong Yu
- Department of Oncology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
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Luo J, Zhang S, Tan M, Li J, Xu H, Tan Y, Huang Y. Targeted molecular profiling of genetic alterations in colorectal cancer using next-generation sequencing. Oncol Lett 2020; 19:1137-1144. [PMID: 31966042 PMCID: PMC6955650 DOI: 10.3892/ol.2019.11203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 10/10/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a major contributor to cancer-associated mortality in China and remains a vast challenge worldwide. Although the genetic basis of CRC has been investigated, the uncommonly mutated genes in CRC remain unknown, in particular in the Asian population. In the present study, targeted region sequencing on 22 CRC and 10 paired non-cancerous tissues was performed to determine the genetic pattern of CRC samples in the Chinese population. Driver genes were detected by three distinct softwares, including MutSigCV, oncodriveFM and iCAGES. A total of 1,335 reliable somatic mutations were identified in tumour samples compared with normal samples. Furthermore, mismatch repair (MMR) mutant patients presented significantly higher mutation density compared with MMR wild-type patients. The results from MutSigCV, oncodriveFM and iCAGES analyses simultaneously detected 29 unique driver genes. In addition, the genes APC regulator of WNT signaling pathway, SMAD family member 4, neurofibromin 1, AT-rich interaction domain 5B and nuclear receptor corepressor 1 were the top five most frequently mutated genes in CRC samples, with mutation rates of 68, 36, 36, 32 and 27%, respectively. The findings from the present study may therefore serve as a basis for future investigation on the diagnosis and oncogenesis of CRC.
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Affiliation(s)
- Jia Luo
- Department of Gastroenterology, The Sanming First Hospital Affiliated to Fujian Medical University, Sanming, Fujian 365000, P.R. China
| | - Shengjun Zhang
- Department of Gastroenterology, The Sanming First Hospital Affiliated to Fujian Medical University, Sanming, Fujian 365000, P.R. China
| | - Meihua Tan
- BGI Education Center, University of Chinese Academy of Sciences, Beijing 100049, P.R. China
| | - Jia Li
- Department of Thyroid and Breast, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, P.R. China
| | - Huadong Xu
- Department of Gastroenterology, The Sanming First Hospital Affiliated to Fujian Medical University, Sanming, Fujian 365000, P.R. China
| | - Yanfei Tan
- Institute of Stem Cell Medicine, Fujian Medical University, Fuzhou, Fujian 350108, P.R. China
| | - Yue Huang
- Department of Gastroenterology, The Sanming First Hospital Affiliated to Fujian Medical University, Sanming, Fujian 365000, P.R. China
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11
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Guo Z, Sui L, Qi J, Sun Q, Xu Y, Zou N, Xie Y, Kong Y. miR-196b inhibits cell migration and invasion through targeting MAP3K1 in hydatidiform mole. Biomed Pharmacother 2019; 113:108760. [PMID: 30889489 DOI: 10.1016/j.biopha.2019.108760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 03/01/2019] [Accepted: 03/05/2019] [Indexed: 02/07/2023] Open
Abstract
MicroRNAs (miRNAs) are a class of small non-coding RNAs that are closely associated with carcinogenesis. Accumulating data indicate that miR-196b participates in the development of various types of cancers. However, the role of miR-196b in the formation of hydatidiform mole (HM) is still unclear. Our previous studies have demonstrated that miR-196b levels were decreased in JAR and BeWo cells and in HM tissue samples, as demonstrated by RT-PCR analysis. Furthermore, we discovered that overexpression of miR-196b in JAR and BeWo cells inhibited cellular proliferation, migration and invasion, as shown by Cell counting kit-8 (CCK-8) and transwell assays, respectively. Subsequently, we explored the interaction of miR-196b with its target gene in human choriocarcinoma cell lines. MAP3K1 is a target gene predicted by bioinformatic analysis that was previously shown to exhibit reduced expression levels following treatment with miR-196b in JAR and BeWo cells. We demonstrated that MAP3K1 was a direct target of miR-196b using the dual-luciferase reporter assay in Hela cells. In summary, the present study demonstrated that miR-196b suppressed proliferation, migration and invasion of human choriocarcinoma cells by inhibiting its transcriptional target MAP3K1. miR-196b and MAP3K1 may be considered potential targets for the clinical treatment of HM.
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Affiliation(s)
- Zhenzhen Guo
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Linlin Sui
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Jia Qi
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Qiannan Sun
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Yuefei Xu
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
| | - Na Zou
- Department of Pathology, Dalian Municipal Women and Children's Medical Center, Dalian 116044, Liaoning, China.
| | - Yunpeng Xie
- Dalian Med Univ, First Affiliated Hosp, Inst Cardiovasc Dis, Dept Cardiol, Dalian 116044116021, Liaoning, China.
| | - Ying Kong
- Core Lab Glycobiol & Glycoengn, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.
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12
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Diab M, Azmi A, Mohammad R, Philip PA. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother 2018; 20:535-546. [PMID: 30592647 DOI: 10.1080/14656566.2018.1561869] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. AREAS COVERED This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. EXPERT OPINION Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.
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Affiliation(s)
- Maria Diab
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Asfar Azmi
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Ramzi Mohammad
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Philip A Philip
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA.,b Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA
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13
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Avivar-Valderas A, McEwen R, Taheri-Ghahfarokhi A, Carnevalli LS, Hardaker EL, Maresca M, Hudson K, Harrington EA, Cruzalegui F. Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer. Oncotarget 2018; 9:21444-21458. [PMID: 29765551 PMCID: PMC5940413 DOI: 10.18632/oncotarget.25118] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 03/22/2018] [Indexed: 12/30/2022] Open
Abstract
The PI3Kα signaling pathway is frequently hyper-activated in breast cancer (BrCa), as a result of mutations/amplifications in oncogenes (e.g. HER2), decreased function in tumor suppressors (e.g. PTEN) or activating mutations in key components of the pathway. In particular, activating mutations of PIK3CA (~45%) are frequently found in luminal A BrCa samples. Genomic studies have uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (~8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples. Further, simultaneous mutation of PIK3CA and MAP3K1 are found in ~11% of mutant PIK3CA tumors. How these two alterations may cooperate to elicit tumorigenesis and impact the sensitivity to PI3K and AKT inhibitors is currently unknown. Using CRISPR gene editing we have genetically disrupted MAP3K1 expression in mutant PIK3CA cell lines to specifically create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1 deficient cell lines exhibited ~2.4-fold increased proliferation rate and decreased sensitivity to PI3Kα/δ(AZD8835) and AKT (AZD5363) inhibitors (~2.61 and ~5.23-fold IC50 increases, respectively) compared with parental control cell lines. In addition, mechanistic analysis revealed that MAP3K1 disruption enhances AKT phosphorylation and downstream signaling and reduces sensitivity to AZD5363-mediated pathway inhibition. This appears to be a consequence of deficient MAP3K1-JNK signaling increasing IRS1 stability and therefore promoting IRS1 binding to p85, resulting in enhanced PI3Kα activity. Using 3D-MCF10A-PI3KαH1047R models, we found that MAP3K1 depletion increased overall acinar volume and counteracted AZD5363-mediated reduction of acinar growth due to enhanced proliferation and reduced apoptosis. Furthermore, in vivo efficacy studies revealed that MAP3K1-deficient MCF7 tumors were less sensitive to AKT inhibitor treatment, compared with parental MCF7 tumors. Our study provides mechanistic and in vivo evidence indicating a role for MAP3K1 as a tumor suppressor gene at least in the context of PIK3CA-mutant backgrounds. Further, our work predicts that MAP3K1 mutational status may be considered as a predictive biomarker for efficacy in PI3K pathway inhibitor trials.
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Affiliation(s)
- Alvaro Avivar-Valderas
- Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.,Current address: TiGenix, Parque Tecnológico de Madrid, Tres Cantos, Madrid, Spain
| | - Robert McEwen
- Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK
| | - Amir Taheri-Ghahfarokhi
- Translational Genomics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | | | | | - Marcello Maresca
- Translational Genomics, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| | - Kevin Hudson
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.,Current address: 2TheNth, Adelphi Mill, Bollington, Macclesfield, UK
| | | | - Francisco Cruzalegui
- Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK.,Current address: Pierre Fabre R&D Centre, Toulouse, France
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14
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Marqus S, Pirogova E, Piva TJ. Evaluation of the use of therapeutic peptides for cancer treatment. J Biomed Sci 2017; 24:21. [PMID: 28320393 PMCID: PMC5359827 DOI: 10.1186/s12929-017-0328-x] [Citation(s) in RCA: 345] [Impact Index Per Article: 43.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 03/14/2017] [Indexed: 12/25/2022] Open
Abstract
Cancer along with cardiovascular disease are the main causes of death in the industrialised countries around the World. Conventional cancer treatments are losing their therapeutic uses due to drug resistance, lack of tumour selectivity and solubility and as such there is a need to develop new therapeutic agents. Therapeutic peptides are a promising and a novel approach to treat many diseases including cancer. They have several advantages over proteins or antibodies: as they are (a) easy to synthesise, (b) have a high target specificity and selectivity and (c) have low toxicity. Therapeutic peptides do have some significant drawbacks related to their stability and short half-life. In this review, strategies used to overcome peptide limitations and to enhance their therapeutic effect will be compared. The use of short cell permeable peptides that interfere and inhibit protein-protein interactions will also be evaluated.
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Affiliation(s)
- Susan Marqus
- School of Engineering, RMIT University, Bundoora, VIC 3083 Australia
| | - Elena Pirogova
- School of Engineering, RMIT University, Bundoora, VIC 3083 Australia
| | - Terrence J. Piva
- School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083 Australia
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15
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Liu C, Wang S, Zhu S, Wang H, Gu J, Gui Z, Jing J, Hou X, Shao Y. MAP3K1-targeting therapeutic artificial miRNA suppresses the growth and invasion of breast cancer in vivo and in vitro. SPRINGERPLUS 2016; 5:11. [PMID: 26759750 PMCID: PMC4700027 DOI: 10.1186/s40064-015-1597-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 12/07/2015] [Indexed: 01/11/2023]
Abstract
Recent investigations have highlighted that therapeutic artificial microRNAs could be promising candidates for cancer therapy through the modulation of tumor promoter or suppressor. MEK kinase 1 (MEKK1) is expressed by mitogen-activated kinase kinase kinase 1 (MAP3K1), an important kinase that links Ras activation to MAPK signaling. In the present study, we showed that synthetic MAP3K1-targeting artificial miRNA may provide considerable beneficial effects in the prevention of breast cancer growth and metastasis. We showed that MEKK1 was highly expressed in human breast cancer specimens, compared with adjacent normal tissues. Using a miRNA-expressing lentivirus system, we delivered a artificial miRNA (Map3k1 amiRNA) that targets MAP3K1 into 4T1 breast cancer cells and investigated the impact of MAP3K1-targeting miRNA on the growth and invasive behavior of breast cancer in vitro and in vivo. We found that overexpression of Map3k1 amiRNA led to impaired activities of p-ERK and p-p38. In addition, Map3k1 amiRNA induced marked proliferative impairment and invasive attenuation in breast cancer cells. However, Map3k1 amiRNA did not have evident influence on the apoptotic response of 4T1 cells. Moreover, using in vivo nude mice model, we identified that Map3k1 amiRNA attenuated tumor growth and lung metastasis of breast cancer cells. Taken together, our findings explicitly indicated that MEKK1 exerted important oncogenic property in breast cancer development, and MAP3K1-targeting artificial miRNA may provide promising therapeutic effects in the treatment of breast cancer.
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Affiliation(s)
- Chun Liu
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
| | - Shengjie Wang
- Kangda College of Nanjing Medical University, 88 Chunhui Road, Lianyungang, Jiangsu People's Republic of China
| | - Shunxing Zhu
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
| | - Haifeng Wang
- Kangda College of Nanjing Medical University, 88 Chunhui Road, Lianyungang, Jiangsu People's Republic of China
| | - Jiayi Gu
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
| | - Zeping Gui
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
| | - Jin Jing
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
| | - Xiaofan Hou
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
| | - Yixiang Shao
- Laboratory animal center of Nantong University, 19 Qixiu Road, Nantong, Jiangsu People's Republic of China
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16
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Singh R, Lillard JW, Singh S. Epigenetic Changes and Potential Targets in Pancreatic Cancer. EPIGENETIC ADVANCEMENTS IN CANCER 2016:27-63. [DOI: 10.1007/978-3-319-24951-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Suddason T, Gallagher E. A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1. Cell Death Differ 2015; 22:540-8. [PMID: 25613373 PMCID: PMC4356348 DOI: 10.1038/cdd.2014.239] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Revised: 12/15/2014] [Accepted: 12/17/2014] [Indexed: 12/26/2022] Open
Abstract
Despite the sizable number of components that comprise Mapk cascades, Map3k1 is the only element that contains both a kinase domain and a plant homeodomain (PHD) motif, allowing Map3k1 to regulate the protein phosphorylation and ubiquitin proteasome systems. As such, Map3k1 has complex roles in the regulation of cell death, survival, migration and differentiation. Numerous mouse and human genetic analyses have demonstrated that Map3k1 is of critical importance for the immune system, cardiac tissue, testis, wound healing, tumorigenesis and cancer. Recent gene knockin of Map3k1 to mutate the E2 binding site within the Map3k1 PHD motif and high throughput ubiquitin protein array screening for Map3k1 PHD motif substrates provide critical novel insights into Map3k1 PHD motif signal transduction and bring a brand-new understanding to Map3k1 signaling in mammalian biology.
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Affiliation(s)
- T Suddason
- Department of Medicine, Imperial College London, Du Cane Road, London, UK
| | - E Gallagher
- Department of Medicine, Imperial College London, Du Cane Road, London, UK
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18
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Glubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, Carlebur S, O'Reilly M, Betts JA, Hillman KM, Kaufmann S, Beesley J, Canisius S, Hopper JL, Southey MC, Tsimiklis H, Apicella C, Schmidt MK, Broeks A, Hogervorst FB, van der Schoot CE, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Ruebner M, Ekici AB, Beckmann MW, Peto J, dos-Santos-Silva I, Fletcher O, Johnson N, Pharoah PDP, Bolla MK, Wang Q, Dennis J, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Burwinkel B, Marme F, Yang R, Surowy H, Guénel P, Truong T, Menegaux F, Sanchez M, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, González-Neira A, Benitez J, Zamora MP, Arias Perez JI, Anton-Culver H, Neuhausen SL, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Meindl A, Schmutzler RK, Brauch H, Ko YD, Brüning T, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Tanaka H, Dörk T, Bogdanova NV, Helbig S, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Zhao H, Weltens C, van Limbergen E, Chang-Claude J, Flesch-Janys D, Rudolph A, Seibold P, Radice P, Peterlongo P, Barile M, et alGlubb DM, Maranian MJ, Michailidou K, Pooley KA, Meyer KB, Kar S, Carlebur S, O'Reilly M, Betts JA, Hillman KM, Kaufmann S, Beesley J, Canisius S, Hopper JL, Southey MC, Tsimiklis H, Apicella C, Schmidt MK, Broeks A, Hogervorst FB, van der Schoot CE, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Ruebner M, Ekici AB, Beckmann MW, Peto J, dos-Santos-Silva I, Fletcher O, Johnson N, Pharoah PDP, Bolla MK, Wang Q, Dennis J, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Burwinkel B, Marme F, Yang R, Surowy H, Guénel P, Truong T, Menegaux F, Sanchez M, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, González-Neira A, Benitez J, Zamora MP, Arias Perez JI, Anton-Culver H, Neuhausen SL, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Meindl A, Schmutzler RK, Brauch H, Ko YD, Brüning T, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Tanaka H, Dörk T, Bogdanova NV, Helbig S, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Zhao H, Weltens C, van Limbergen E, Chang-Claude J, Flesch-Janys D, Rudolph A, Seibold P, Radice P, Peterlongo P, Barile M, Capra F, Couch FJ, Olson JE, Hallberg E, Vachon C, Giles GG, Milne RL, McLean C, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, See MH, Cornes B, Cheng CY, Ikram MK, Kristensen V, Zheng W, Halverson SL, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Devilee P, Tollenaar RAEM, Seynaeve C, Van Asperen CJ, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Klevebring D, Darabi H, Eriksson M, Hooning MJ, Hollestelle A, Martens JWM, Collée JM, Hall P, Li J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Cross SS, Reed MWR, Blot W, Signorello LB, Cai Q, Shah M, Ghoussaini M, Kang D, Choi JY, Park SK, Noh DY, Hartman M, Miao H, Lim WY, Tang A, Hamann U, Torres D, Jakubowska A, Lubinski J, Jaworska K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Olswold C, Slager S, Toland AE, Yannoukakos D, Shen CY, Wu PE, Yu JC, Hou MF, Swerdlow A, Ashworth A, Orr N, Jones M, Pita G, Alonso MR, Álvarez N, Herrero D, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Ahmed S, Healey CS, Brown MA, Ponder BAJ, Chenevix-Trench G, Thompson DJ, Edwards SL, Easton DF, Dunning AM, French JD. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. Am J Hum Genet 2015; 96:5-20. [PMID: 25529635 PMCID: PMC4289692 DOI: 10.1016/j.ajhg.2014.11.009] [Show More Authors] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 11/17/2014] [Indexed: 01/04/2023] Open
Abstract
Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
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Affiliation(s)
- Dylan M Glubb
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Mel J Maranian
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Kyriaki Michailidou
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Karen A Pooley
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Kerstin B Meyer
- Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Siddhartha Kar
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Saskia Carlebur
- Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Martin O'Reilly
- Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | - Joshua A Betts
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
| | - Kristine M Hillman
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Susanne Kaufmann
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Jonathan Beesley
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia
| | - Sander Canisius
- Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Melissa C Southey
- Department of Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Helen Tsimiklis
- Department of Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Carmel Apicella
- Department of Pathology, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Marjanka K Schmidt
- Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands
| | - Annegien Broeks
- Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands
| | - Frans B Hogervorst
- Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands
| | | | - Kenneth Muir
- Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK; Institute of Population Health, University of Manchester, Manchester M13 9PL, UK
| | - Artitaya Lophatananon
- Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK
| | - Sarah Stewart-Brown
- Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK
| | | | - Peter A Fasching
- University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany; Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Matthias Ruebner
- University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Matthias W Beckmann
- University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, 91054 Erlangen, Germany
| | - Julian Peto
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Isabel dos-Santos-Silva
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Olivia Fletcher
- Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK
| | - Nichola Johnson
- Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK
| | - Paul D P Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Manjeet K Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Elinor J Sawyer
- Research Oncology, Division of Cancer Studies, King's College London, Guy's Hospital, London SE1 9RT, UK
| | - Ian Tomlinson
- Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford OX3 7BN, UK
| | - Michael J Kerin
- Clinical Science Institute, University Hospital Galway, Galway, Ireland
| | - Nicola Miller
- Clinical Science Institute, University Hospital Galway, Galway, Ireland
| | - Barbara Burwinkel
- Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany
| | - Frederik Marme
- Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany; National Center for Tumor Diseases, University of Heidelberg, 69120 Heidelberg, Germany
| | - Rongxi Yang
- Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany; Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Harald Surowy
- Department of Obstetrics and Gynecology, University of Heidelberg, 69115 Heidelberg, Germany; Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Pascal Guénel
- Institut National de la Santé et de la Recherche Médicale U1018, Environmental Epidemiology of Cancers, Centre de Recherche en Epidémiologie et Santé des Populations, 94807 Villejuif, France; UMRS 1018, University Paris-Sud, 94807 Villejuif, France
| | - Thérèse Truong
- Institut National de la Santé et de la Recherche Médicale U1018, Environmental Epidemiology of Cancers, Centre de Recherche en Epidémiologie et Santé des Populations, 94807 Villejuif, France; UMRS 1018, University Paris-Sud, 94807 Villejuif, France
| | - Florence Menegaux
- Institut National de la Santé et de la Recherche Médicale U1018, Environmental Epidemiology of Cancers, Centre de Recherche en Epidémiologie et Santé des Populations, 94807 Villejuif, France; UMRS 1018, University Paris-Sud, 94807 Villejuif, France
| | - Marie Sanchez
- Institut National de la Santé et de la Recherche Médicale U1018, Environmental Epidemiology of Cancers, Centre de Recherche en Epidémiologie et Santé des Populations, 94807 Villejuif, France; UMRS 1018, University Paris-Sud, 94807 Villejuif, France
| | - Stig E Bojesen
- Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Børge G Nordestgaard
- Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Sune F Nielsen
- Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
| | - Henrik Flyger
- Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark
| | - Anna González-Neira
- Centro Nacional de Genotipado Human Genotyping Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
| | - Javier Benitez
- Centro de Investigación en Red de Enfermedades Raras, 46010 Valencia, Spain; Human Genetics Group, Spanish National Cancer Centre and Biomedical Network on Rare Diseases, 28029 Madrid, Spain
| | - M Pilar Zamora
- Servicio de Oncología Médica, Hospital Universitario La Paz, 28029 Madrid, Spain
| | | | - Hoda Anton-Culver
- Department of Epidemiology, University of California, Irvine, Irvine, CA 92697, USA
| | | | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, 69120 Heidelberg, Germany; German Cancer Consortium, 69120 Heidelberg, Germany
| | - Aida Karina Dieffenbach
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, 69120 Heidelberg, Germany; German Cancer Consortium, 69120 Heidelberg, Germany
| | - Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, 69120 Heidelberg, Germany
| | | | - Alfons Meindl
- Division of Gynaecology and Obstetrics, Technische Universität München, 81675 Munich, Germany
| | - Rita K Schmutzler
- Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, 50931 Cologne, Germany; Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology, Center for Molecular Medicine Cologne, University Hospital of Cologne, 50937 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50923 Cologne, Germany; Center for Integrated Oncology, Medical Faculty, University Hospital of Cologne, 50937 Cologne, Germany
| | - Hiltrud Brauch
- University of Tübingen, 72074 Tübingen, Germany; Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany
| | - Yon-Dschun Ko
- Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, 53113 Bonn, Germany
| | - Thomas Brüning
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, 44789 Bochum, Germany
| | - Heli Nevanlinna
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, 00029 Helsinki, Finland
| | - Taru A Muranen
- Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, 00029 Helsinki, Finland
| | - Kristiina Aittomäki
- Department of Clinical Genetics, Helsinki University Central Hospital, 00029 Helsinki, Finland
| | - Carl Blomqvist
- Department of Oncology, University of Helsinki and Helsinki University Central Hospital, 00029 Helsinki, Finland
| | - Keitaro Matsuo
- Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hidemi Ito
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
| | - Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Hideo Tanaka
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
| | - Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
| | - Natalia V Bogdanova
- Department of Radiation Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Sonja Helbig
- Gynaecology Research Unit, Hannover Medical School, 30625 Hannover, Germany
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Sara Margolin
- Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Arto Mannermaa
- Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70211 Kuopio, Finland; School of Medicine, Institute of Clinical Medicine, Pathology, and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland
| | - Vesa Kataja
- Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70211 Kuopio, Finland; School of Medicine, Institute of Clinical Medicine, Pathology, and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland; Cancer Center, Kuopio University Hospital, 70211 Kuopio, Finland
| | - Veli-Matti Kosma
- Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70211 Kuopio, Finland; School of Medicine, Institute of Clinical Medicine, Pathology, and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland
| | - Jaana M Hartikainen
- Cancer Center of Eastern Finland, University of Eastern Finland, 70211 Kuopio, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, 70211 Kuopio, Finland; School of Medicine, Institute of Clinical Medicine, Pathology, and Forensic Medicine, University of Eastern Finland, 70211 Kuopio, Finland
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | - Chiu-chen Tseng
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | - David Van Den Berg
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | - Daniel O Stram
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium; Vesalius Research Center, VIB, 3000 Leuven, Belgium
| | - Hui Zhao
- Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium; Vesalius Research Center, VIB, 3000 Leuven, Belgium
| | | | | | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Dieter Flesch-Janys
- Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Anja Rudolph
- Division of Cancer Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Petra Seibold
- Division of Cancer Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Istituto Nazionale Tumori, Fondazione Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Paolo Peterlongo
- Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy
| | - Monica Barile
- Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, 20141 Milan, Italy
| | - Fabio Capra
- Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy; Cogentech Cancer Genetic Test Laboratory, 20139 Milan, Italy
| | - Fergus J Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
| | - Janet E Olson
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Emily Hallberg
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Celine Vachon
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Graham G Giles
- Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia
| | - Roger L Milne
- Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, 1066 CX Amsterdam, the Netherlands; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia
| | - Catriona McLean
- Anatomical Pathology, The Alfred, Melbourne, VIC 3004, Australia
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | - Brian E Henderson
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | - Fredrick Schumacher
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90089, USA
| | | | - Jacques Simard
- Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC G1V 4G2, Canada
| | - Mark S Goldberg
- Division of Clinical Epidemiology, McGill University Health Centre, Royal Victoria Hospital, Montreal, QC H3A 1A1, Canada; Department of Medicine, McGill University, Montreal, QC H3A 1A1, Canada
| | - France Labrèche
- Département de Médecine Sociale et Préventive, Département de Santé Environnementale et Santé au Travail, Université de Montréal, Montreal, QC H3A 3C2, Canada
| | - Martine Dumont
- Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, QC G1V 4G2, Canada
| | - Soo Hwang Teo
- Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 47500 Subang Jaya, Malaysia; Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
| | - Cheng Har Yip
- Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
| | - Mee-Hoong See
- Breast Cancer Research Unit, University Malaya Cancer Research Institute, University Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
| | - Belinda Cornes
- Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Singapore
| | - Ching-Yu Cheng
- Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Singapore
| | - M Kamran Ikram
- Singapore Eye Research Institute, National University of Singapore, Singapore 168751, Singapore
| | - Vessela Kristensen
- Institute of Clinical Medicine, University of Oslo, 0450 Oslo, Norway; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, 0310 Oslo, Norway; Department of Clinical Molecular Biology, University of Oslo, 0450 Oslo, Norway
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Sandra L Halverson
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Martha Shrubsole
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Robert Winqvist
- Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu, Oulu University Hospital, 90210 Oulu, Finland
| | - Katri Pylkäs
- Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, NordLab Oulu, Oulu University Hospital, 90210 Oulu, Finland
| | - Arja Jukkola-Vuorinen
- Department of Oncology, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland
| | - Saila Kauppila
- Department of Pathology, Oulu University Hospital, University of Oulu, 90014 Oulu, Finland
| | - Irene L Andrulis
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1X5, Canada
| | - Julia A Knight
- Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada; Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Gord Glendon
- Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Sandrine Tchatchou
- Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Peter Devilee
- Departments of Human Genetics and Pathology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Robert A E M Tollenaar
- Departments of Human Genetics and Pathology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Caroline Seynaeve
- Family Cancer Clinic, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
| | - Christi J Van Asperen
- Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands
| | - Montserrat García-Closas
- Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK; Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK
| | - Jonine Figueroa
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20892, USA
| | - Jolanta Lissowska
- Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, 02-781 Warsaw, Poland
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Daniel Klevebring
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Hatef Darabi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Mikael Eriksson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Maartje J Hooning
- Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, 3075 EA Rotterdam, the Netherlands
| | - Antoinette Hollestelle
- Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, 3075 EA Rotterdam, the Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, 3075 EA Rotterdam, the Netherlands
| | - J Margriet Collée
- Department of Clinical Genetics, Erasmus University Medical Center, 3008 AE Rotterdam, the Netherlands
| | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Jingmei Li
- Human Genetics Division, Genome Institute of Singapore, Singapore 138672, Singapore
| | - Keith Humphreys
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Xiao-Ou Shu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Wei Lu
- Shanghai Center for Disease Control and Prevention, Changning, Shanghai 200336, China
| | - Yu-Tang Gao
- Department of Epidemiology, Shanghai Cancer Institute, Shanghai 200032, China
| | - Hui Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Angela Cox
- Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK
| | - Simon S Cross
- Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2RX, UK
| | - Malcolm W R Reed
- Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK
| | - William Blot
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA; International Epidemiology Institute, Rockville, MD 20850, USA
| | - Lisa B Signorello
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA; International Epidemiology Institute, Rockville, MD 20850, USA
| | - Qiuyin Cai
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA
| | - Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Maya Ghoussaini
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Daehee Kang
- Department of Preventive Medicine, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University, Seoul 110-799, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
| | - Ji-Yeob Choi
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
| | - Sue K Park
- Department of Preventive Medicine, Seoul National University College of Medicine and Cancer Research Institute, Seoul National University, Seoul 110-799, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 151-742, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea
| | - Dong-Young Noh
- Department of Surgery, Seoul National University, Bundang Hospital, Seongnam 110-744, Korea
| | - Mikael Hartman
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore 119228, Singapore
| | - Hui Miao
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore
| | - Wei Yen Lim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore
| | - Anthony Tang
- Division of General Surgery, National University Health System, Singapore 119228, Singapore
| | - Ute Hamann
- Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Diana Torres
- Molecular Genetics of Breast Cancer, German Cancer Research Center, 69120 Heidelberg, Germany; Institute of Human Genetics, Pontificia Universidad Javeriana, Bogotá 11001000, Colombia
| | - Anna Jakubowska
- Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
| | - Jan Lubinski
- Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
| | - Katarzyna Jaworska
- Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
| | - Katarzyna Durda
- Department of Genetics and Pathology, Pomeranian Medical University, 70-115 Szczecin, Poland
| | | | | | - Paul Brennan
- International Agency for Research on Cancer, 69372 Lyon, France
| | - James McKay
- International Agency for Research on Cancer, 69372 Lyon, France
| | - Curtis Olswold
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Susan Slager
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Amanda E Toland
- Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, OH 43210, USA
| | - Drakoulis Yannoukakos
- Molecular Diagnostics Laboratory, Institute of Radioisotopes and Radiodiagnostic Products, National Centre for Scientific Research "Demokritos," Aghia Paraskevi Attikis, Athens 15310, Greece
| | - Chen-Yang Shen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; School of Public Health, China Medical University, Taichung 40402, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Pei-Ei Wu
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Taiwan Biobank, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Jyh-Cherng Yu
- Department of Surgery, Tri-Service General Hospital, Taipei 114, Taiwan
| | - Ming-Feng Hou
- Cancer Center and Department of Surgery, Kaohsiung Medical University, Chung-Ho Memorial Hospital, Kaohsiung 807, Taiwan
| | - Anthony Swerdlow
- Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK; Division of Breast Cancer Research, Institute of Cancer Research, Sutton SM2 5NG, UK
| | - Alan Ashworth
- Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK
| | - Nick Orr
- Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK
| | - Michael Jones
- Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton SM2 5NG, UK
| | - Guillermo Pita
- Centro Nacional de Genotipado Human Genotyping Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
| | - M Rosario Alonso
- Centro Nacional de Genotipado Human Genotyping Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
| | - Nuria Álvarez
- Centro Nacional de Genotipado Human Genotyping Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
| | - Daniel Herrero
- Centro Nacional de Genotipado Human Genotyping Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre, 28029 Madrid, Spain
| | - Daniel C Tessier
- McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada
| | - Daniel Vincent
- McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada
| | - Francois Bacot
- McGill University and Génome Québec Innovation Centre, Montreal, QC H3A 0G1, Canada
| | - Craig Luccarini
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Caroline Baynes
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Shahana Ahmed
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Catherine S Healey
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
| | - Melissa A Brown
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
| | - Bruce A J Ponder
- Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
| | | | - Deborah J Thompson
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Stacey L Edwards
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia
| | - Douglas F Easton
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Alison M Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
| | - Juliet D French
- Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
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Tormos AM, Taléns-Visconti R, Nebreda AR, Sastre J. p38 MAPK: a dual role in hepatocyte proliferation through reactive oxygen species. Free Radic Res 2013; 47:905-16. [PMID: 23906070 DOI: 10.3109/10715762.2013.821200] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
p38 MAPKs are important mediators of signal transduction that respond to a wide range of extracellular stressors such as UV radiation, osmotic shock, hypoxia, pro-inflammatory cytokines, and oxidative stress. The most abundant family member is p38α, which helps to couple cell proliferation and growth in response to certain damaging stimuli. In fact, increased proliferation and impaired differentiation are hallmarks of p38α-deficient cells. It has been reported that reactive oxygen species (ROS) play a critical role in cytokine-induced p38α activation. Under physiological conditions, p38α can function as a mediator of ROS signaling and either activate or suppress cell cycle progression depending on the activation stimulus. The interplay between cell proliferation, p38 MAPK activation, and ROS production plays an important role in hepatocytes. In fact, low levels of ROS seem to be needed to activate several signaling pathways in response to hepatectomy and to orchestrate liver regeneration. p38 MAPK works as a sensor of oxidative stress and cells that have developed mechanisms to uncouple p38 MAPK activation from oxidative stress are more likely to become tumorigenic. So far, p38α influences the redox balance, determining cell survival, terminal differentiation, proliferation, and senescence. Further studies would be necessary in order to clarify the precise role of p38 MAPK signaling as a redox therapeutical target.
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Affiliation(s)
- A M Tormos
- Department of Physiology, Faculty of Pharmacy, University of Valencia , Valencia , Spain
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20
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Feldmann G, Mishra A, Bisht S, Karikari C, Garrido-Laguna I, Rasheed Z, Ottenhof NA, Dadon T, Alvarez H, Fendrich V, Rajeshkumar NV, Matsui W, Brossart P, Hidalgo M, Bannerji R, Maitra A, Nelkin BD. Cyclin-dependent kinase inhibitor Dinaciclib (SCH727965) inhibits pancreatic cancer growth and progression in murine xenograft models. Cancer Biol Ther 2011; 12:598-609. [PMID: 21768779 DOI: 10.4161/cbt.12.7.16475] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most lethal of human malignancies, and potent therapeutic options are lacking. Inhibition of cell cycle progression through pharmacological blockade of cyclin-dependent kinases (CDK) has been suggested as a potential treatment option for human cancers with deregulated cell cycle control. Dinaciclib (SCH727965) is a novel small molecule multi-CDK inhibitor with low nanomolar potency against CDK1, CDK2, CDK5 and CDK9 that has shown favorable toxicity and efficacy in preliminary mouse experiments, and has been well tolerated in Phase I clinical trials. In the current study, the therapeutic efficacy of SCH727965 on human pancreatic cancer cells was tested using in vitro and in vivo model systems. Treatment with SCH727965 significantly reduced in vitro cell growth, motility and colony formation in soft agar of MIAPaCa-2 and Pa20C cells. These phenotypic changes were accompanied by marked reduction of phosphorylation of Retinoblastoma (Rb) and reduced activation of RalA. Single agent therapy with SCH727965 (40 mg/kg i.p. twice weekly) for 4 weeks significantly reduced subcutaneous tumor growth in 10/10 (100%) of tested low-passage human pancreatic cancer xenografts. Treatment of low passage pancreatic cancer xenografts with a combination of SCH727965 and gemcitabine was significantly more effective than either agent alone. Gene Set Enrichment Analysis identified overrepresentation of the Notch and Transforming Growth Factor-β (TGF-β) signaling pathways in the xenografts least responsive to SCH727965 treatment. Treatment with the cyclin-dependent kinase inhibitor SCH727965 alone or in combination is a highly promising novel experimental therapeutic strategy against pancreatic cancer.
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Affiliation(s)
- Georg Feldmann
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Cytotoxic responses to N-(4-hydroxyphenyl)retinamide in human pancreatic cancer cells. Cancer Chemother Pharmacol 2010; 68:477-87. [PMID: 21072519 DOI: 10.1007/s00280-010-1504-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 10/26/2010] [Indexed: 10/18/2022]
Abstract
PURPOSE Although fenretinide (4-HPR) has been studied in breast cancer and in neuroblastoma, little is known regarding its activity in pancreatic cancer, a neoplasm for which there are few therapeutic options. Since pancreatic cancer cells are susceptible to reactive oxygen species (ROS) and ceramide, two hallmarks of 4-HPR cytotoxicity, we investigated the effect of 4-HPR on human pancreatic cancer cells. METHODS Human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 were treated with 4-HPR, followed by measurement of viability, proliferation, ROS and ceramide production, and Western blotting. RESULTS At the measured IC(50) of 10 μM, 4-HPR led to a 44-68% reduction in [(3)H]thymidine incorporation, a >3-fold increase in de novo ceramide levels, a 2.7-fold increase in ROS, and minor increases in markers of apoptosis. 4-HPR induced a robust, sustained increase in LC3 II expression and enhanced formation of acridine orange-stained acidic vesicles that are markers of autophagy. In addition, sustained, dose-dependent increases in JNK and p38 phosphorylation and decreased ERK phosphorylation were observed following treatment. Pretreatment with vitamin E, a ROS scavenger, and 3-methyladenine, an autophagy inhibitor, individually led to decreased sensitivity to 4-HPR; however, the de novo ceramide inhibitor myriocin had no effect. CONCLUSIONS These data show that 4-HPR triggers pancreatic cancer cell death by apoptosis and autophagy and that sensitivity appears to be mediated by ROS and not ceramide. This study is the first to characterize the response of human pancreatic cancer cells to 4-HPR and opens the door to investigations into this compound in pancreatic adenocarcinomas.
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Feldmann G, Mishra A, Hong SM, Bisht S, Strock CJ, Ball DW, Goggins M, Maitra A, Nelkin BD. Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling. Cancer Res 2010; 70:4460-9. [PMID: 20484029 PMCID: PMC3071300 DOI: 10.1158/0008-5472.can-09-1107] [Citation(s) in RCA: 137] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cyclin-dependent kinase 5 (CDK5), a neuronal kinase that functions in migration, has been found to be activated in some human cancers in which it has been implicated in promoting metastasis. In this study, we investigated the role of CDK5 in pancreatic cancers in which metastatic disease is most common at diagnosis. CDK5 was widely active in pancreatic cancer cells. Functional ablation significantly inhibited invasion, migration, and anchorage-independent growth in vitro, and orthotopic tumor formation and systemic metastases in vivo. CDK5 blockade resulted in the profound inhibition of Ras signaling through its critical effectors RalA and RalB. Conversely, restoring Ral function rescued the effects of CDK5 inhibition in pancreatic cancer cells. Our findings identify CDK5 as a pharmacologically tractable target to degrade Ras signaling in pancreatic cancer.
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Affiliation(s)
- Georg Feldmann
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Anjali Mishra
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Seung-Mo Hong
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Savita Bisht
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Christopher J. Strock
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Douglas W. Ball
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Department of Medicine, and The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Michael Goggins
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Anirban Maitra
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
| | - Barry D. Nelkin
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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Mihaljevic AL, Michalski CW, Friess H, Kleeff J. Molecular mechanism of pancreatic cancer--understanding proliferation, invasion, and metastasis. Langenbecks Arch Surg 2010; 395:295-308. [PMID: 20237938 DOI: 10.1007/s00423-010-0622-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Accepted: 02/16/2010] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The purpose of this review is to highlight the molecular mechanisms leading to the development and progression of pancreatic ductal adenocarcinoma (PDAC) with particular emphasis on tumor cell proliferation, local invasion, and metastasis. Recent advances in the field of PDAC biology have shed light on the molecular events that trigger PDAC initiation and maintenance. RESULTS It is now clear that apart from the genetic alterations within the tumor cells, interactions of the tumor with its environment are necessary for proliferation and invasion. Interestingly, a number of developmental signaling pathways are reactivated in PDAC. Progress has also been made in the understanding of the molecular events that govern the process of metastasis. CONCLUSION Although our understanding of the mechanisms underlying PDAC pathobiology are more advanced than ever, little progress has been made in the clinical treatment of PDAC, and successful bench-to-bedside transfer of knowledge to boost new treatment options is still unsatisfying.
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Affiliation(s)
- André L Mihaljevic
- Chirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstrasse 22, 81675, Munich, Germany
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Rhim AD, Stanger BZ. Molecular biology of pancreatic ductal adenocarcinoma progression: aberrant activation of developmental pathways. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2010; 97:41-78. [PMID: 21074729 PMCID: PMC3117430 DOI: 10.1016/b978-0-12-385233-5.00002-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Embryonic development marks a period of peak tissue growth and morphogenesis in the mammalian lifecycle. Many of the pathways that underlie cell proliferation and movement are relatively quiescent in adult animals but become reactivated during carcinogenesis. This phenomenon has been particularly well documented in pancreatic cancer, where detailed genetic studies and a robust mouse model have permitted investigators to test the role of various developmental signals in cancer progression. In this chapter, we review current knowledge regarding the signaling pathways that act during pancreatic development and the evidence that the reactivation of developmentally important signals is critical for the pathogenesis of this treatment-refractory malignancy.
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Affiliation(s)
- Andrew D Rhim
- Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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25
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Mihaljevic AL, Esposito I, Friess H, Kleeff J. Molecular biology, models, and histopathology of chronic pancreatitis and pancreatic cancer. Eur Surg 2009. [DOI: 10.1007/s10353-009-0496-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Das KC, Muniyappa H. c-Jun-NH2 terminal kinase (JNK)-mediates AP-1 activation by thioredoxin: phosphorylation of cJun, JunB, and Fra-1. Mol Cell Biochem 2009; 337:53-63. [PMID: 19859790 DOI: 10.1007/s11010-009-0285-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Accepted: 10/08/2009] [Indexed: 12/31/2022]
Abstract
Thioredoxin (Trx) is a small ubiquitous protein, which has been shown to be involved in redox-dependent cellular functions. In this article, we demonstrate that the increased level of Trx induces AP-1 DNA binding in a redox-dependent manner by activating JNK subgroup of MAPKs. The majority of AP-1 DNA binding complex was found to be composed of cJun, JunB, and Fra-1. Increased expression of Trx resulted in phosphorylation of cJun, Jun B, and Fra-1. Further, increased expression of Trx induced the phosphorylation of MKK4 and MKK7 which are upstream kinases of the JNK signaling cascade. In co-transfection studies, AP-1-dependent luciferase reporter vector and pcDNA3-Trx increased luciferase activity demonstrating that increased expression of Trx increases AP-1 transactivation. In addition, dominant-negative JNK kinase (dnJNK/MKK4) or dominant-negative JNK (dnJNK) inhibited Trx-mediated AP-1 transactivation, as well as AP-1 DNA binding. Furthermore, transfection of kinase-dead MEKK1, an initiating kinase of the JNK pathway inhibited Trx-mediated AP-1 transactivation and DNA binding, suggesting that MEKK1 may mediate Trx-induced AP-1 activation. In contrast, wild-type MEKK1 overexpression did not inhibit Trx-mediated AP-1 activation. Taken together, our data demonstrate that increased expression of Trx induces MKK4/MKK7-dependent JNK activation, resulting in enhanced DNA binding, and transactivation of AP-1 transcription factor.
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Affiliation(s)
- Kumuda C Das
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
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Chen F, Beezhold K, Castranova V. JNK1, a potential therapeutic target for hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2009; 1796:242-51. [PMID: 19591900 DOI: 10.1016/j.bbcan.2009.06.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2009] [Revised: 06/21/2009] [Accepted: 06/27/2009] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Despite tremendous efforts to diagnose and institute new treatment regimens, the prognosis is still extremely poor. Therefore, knowledge of the molecular mechanisms governing the initiation, maintenance and progression of HCC is urgently needed. Recently, several groups have attributed an important role for c-Jun N-terminal kinase 1 (JNK1) in the pathogenesis of human HCC and its close association with the expression of HCC signature genes. In this review the various associations between JNK1 and HCC are discussed with the hope that targeting this pivotal kinase may lead to novel therapeutic approaches for this fatal disease.
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Affiliation(s)
- Fei Chen
- Laboratory of Cancer Signaling and Epigenetics, Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA.
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Shin S, Asano T, Yao Y, Zhang R, Claret FX, Korc M, Sabapathy K, Menter DG, Abbruzzese JL, Reddy SAG. Activator protein-1 has an essential role in pancreatic cancer cells and is regulated by a novel Akt-mediated mechanism. Mol Cancer Res 2009; 7:745-754. [PMID: 19435822 DOI: 10.1158/1541-7786.mcr-08-0462] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Activator protein-1 (AP-1) regulates the expression of several genes involved in human tumorigenesis. However, there is little known about this transcription factor in pancreatic ductal adenocarcinoma. We recently found high levels of AP-1-binding activities and multiple AP-1/DNA complexes containing c-Jun, JunD, Fra1, and Fra2 in pancreatic cancer cells. Transient transfection assays indicated that AP-1 was functional and capable of transactivating its gene targets. Furthermore, a c-Jun transactivation mutant inhibited anchorage-dependent and anchorage-independent proliferation, suggesting that AP-1 had an essential role in pancreatic cancer cells. Our study also uncovered a novel mechanism by which protein kinase Akt controls c-Jun activity in pancreatic cancer cells. Indeed, distinct from its known ability to induce c-fos and fra1 and to stabilize c-Jun, Akt appeared to directly regulate the transcriptional activity of c-Jun independently of the phosphorylation sites targeted by c-Jun NH(2)-terminal kinase (Ser(63)/Ser(73)) and glycogen synthase kinase-3 (Thr(239)). Our data also suggest that growth factors might use this Akt-regulated mechanism to potently induce c-Jun targets such as cyclin D1. Collectively, our findings indicate that AP-1 has an important function in pancreatic cancer cells and provide evidence for a previously unknown Akt-mediated mechanism of c-Jun activation.
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Affiliation(s)
- Sonyo Shin
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Takayuki Asano
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Yixin Yao
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ronghua Zhang
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Francois-Xavier Claret
- Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Murray Korc
- Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Kanaga Sabapathy
- Laboratory of Molecular Carcinogenesis, National Cancer Centre, Singapore, Singapore
| | - David G Menter
- Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - James L Abbruzzese
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Shrikanth A G Reddy
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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Nacht M, St Martin TB, Byrne A, Klinger KW, Teicher BA, Madden SL, Jiang Y. Netrin-4 regulates angiogenic responses and tumor cell growth. Exp Cell Res 2008; 315:784-94. [PMID: 19094984 DOI: 10.1016/j.yexcr.2008.11.018] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2008] [Revised: 11/21/2008] [Accepted: 11/23/2008] [Indexed: 10/21/2022]
Abstract
Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.
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Affiliation(s)
- Mariana Nacht
- Genzyme Corporation, 49 New York Avenue, Framingham, MA 01701, USA
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30
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Hilbig A, Oettle H. Gemcitabine in the treatment of metastatic pancreatic cancer. Expert Rev Anticancer Ther 2008; 8:511-23. [PMID: 18402518 DOI: 10.1586/14737140.8.4.511] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gemcitabine (2 ,2 -difluorodeoxycytidine) is a deoxycytidine-analog antimetabolite with broad activity against a variety of solid tumors and lymphoid malignancies. It was approved as standard of care in patients with pancreatic cancer one decade ago, based primarily on improvement in clinical benefit response such as pain reduction, improvement in Karnofsky performance status and increase in body weight. This article gives an overview of the pharmacodynamics and pharmacokinetics of gemcitabine, highlights the clinical activity of gemcitabine and summarizes the treatment options in metastatic pancreatic cancer with focus on gemcitabine-based chemotherapy. The emerging role of combinations of gemcitabine with novel targeted agents, including small-molecule inhibitors and other investigational drugs, is also discussed.
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Affiliation(s)
- Andreas Hilbig
- Department of Medical Hematology & Oncology, Charité School of Medicine, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
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Abstract
Pancreatic cancer represents the fourth leading cause of cancer-related mortality in the United States. The vast majority of patients are diagnosed at advanced stages of the disease, at which time gemcitabine-based chemotherapy is typically offered as the standard of care. However, as investigators have arrived at a greater understanding of pancreatic tumor biology, newer therapeutic agents that "target" specific pathways or molecules governing the growth, spread, and maintenance of tumor cells have gained considerable interest. Erlotinib, an orally bioavailable small molecule inhibitor of the epidermal growth factor receptor, is the first of these targeted compounds to be approved for use in combination with gemcitabine for patients with advanced pancreatic cancer. Other targeted agents, including monoclonal antibodies and small molecule inhibitors aimed at a variety of targets, also have been extensively evaluated, with limited success to date. A newer strategy worth pursuing involves tailoring an individual patient's therapy according to the molecular characteristics of both host and tumor, as has shown promise in other solid tumor types.
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Affiliation(s)
- Andrew H Ko
- Department of Medicine, University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA, USA.
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Ibarz G, Oiry C, Carnazzi E, Crespy P, Escrieut C, Fourmy D, Galleyrand JC, Gagne D, Martinez J. Cholecystokinin 1 receptor modulates the MEKK1-induced c-Jun trans-activation: structural requirements of the receptor. Br J Pharmacol 2007; 147:951-8. [PMID: 16491099 PMCID: PMC1760718 DOI: 10.1038/sj.bjp.0706690] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
In cells overexpressing active MEKK1 to enhance c-Jun trans-activation, expression of rat cholecystokinin 1 receptor increased the activity of c-Jun while in the same experimental conditions overexpression of mouse cholecystokinin 1 receptor repressed it. This differential trans-activation is specific, since it was not observed for either the other overexpressed kinases (MEK, PKA) or for other transcription factors (ATF2, ELK-1, CREB). This differential behaviour was also detected in a human colon adenocarcinoma cell-line naturally producing high levels of endogenous MEKK1. This differential behaviour between the two receptors on the MEKK1-induced c-Jun trans-activation was independent of the activation state of JNK, of the phosphorylation level of c-Jun and of its ability to bind its specific DNA responsive elements. Two amino acids (Val43 and Phe50 in the mouse cholecystokinin 1 receptor, replaced by Leu43 and Ileu50 in the rat cholecystokinin 1 receptor) localized in the first transmembrane domain were found to play a crucial role in this differential behaviour. MEKK1 probably activates a transcriptional partner of c-Jun whose activity is maintained or increased in the presence of the rat cholecystokinin 1 receptor but repressed in the presence of the mouse cholecystokinin 1 receptor.
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Affiliation(s)
- Géraldine Ibarz
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
| | - Catherine Oiry
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
| | - Eric Carnazzi
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
| | - Philippe Crespy
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
| | - Chantal Escrieut
- INSERM U151, Institut Louis Bugnard, Centre Hospitalier Universitaire, Rangueil, Bat L3, 31403 Toulouse Cedex 4, France
| | - Daniel Fourmy
- INSERM U151, Institut Louis Bugnard, Centre Hospitalier Universitaire, Rangueil, Bat L3, 31403 Toulouse Cedex 4, France
| | - Jean Claude Galleyrand
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
| | - Didier Gagne
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
| | - Jean Martinez
- Laboratoire des Aminoacides, Peptides et Protéines (LAPP), CNRS UMR 5810, UMI et UMII, UFR Pharmacie, 15, avenue Charles Flahault, 34093 Montpellier Cedex 5, France
- Author for correspondence:
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Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2006; 20:1218-49. [PMID: 16702400 DOI: 10.1101/gad.1415606] [Citation(s) in RCA: 858] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment.
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Affiliation(s)
- Aram F Hezel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
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Abstract
The prognosis of patients with some kinds of cancers whose patients are often found unresectable upon diagnosis is still dismal. In these fields, development of a new therapeutic modality is needed and gene therapy represents one promising strategy. So far, numerous cancer gene therapy clinical trials based on these principles have been carried out and have shown the safety of such modalities, but have fallen short of the initial expectations to cure cancers. In this review, we would like to make a problem-oriented discussion of current status of cancer gene therapy research by using mainly gastrointestinal cancers as an example. In order to overcome obstacles for full realization of cancer gene therapy, numerous researches have been conducted by many researchers. Various cancer-selective and non-selective genes, as well as lytic viruses themselves have been employed for gene therapy. In the context of gene delivery method, different kinds of viral and non-viral strategies have been utilized. In addition, surrogate assays, such as soluble markers and imaging, have been developed for safer and more informative clinical trials. Many experiments and clinical trials to date have figured out current obstacles for the realization of an effective cancer gene therapy modality. Tireless efforts to overcome such hurdles and continuous infusion of novel concepts into this field should lead to break through technologies and the cure of the patients.
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Affiliation(s)
- Masato Yamamoto
- BMR2-410, 901 19th Street South, Birmingham, AL 35294-2172, USA
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Fauquette V, Perrais M, Cerulis S, Jonckheere N, Ducourouble MP, Aubert JP, Pigny P, Seuningen I. The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells. Biochem J 2005; 386:35-45. [PMID: 15461591 PMCID: PMC1134764 DOI: 10.1042/bj20040706] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The human transmembrane mucin MUC4 is aberrantly expressed in 75% of pancreatic ductal adenocarcinomas, whereas no expression is found in normal pancreas. Therefore MUC4 appears as a useful biological marker for the diagnosis of ductal adenocarcinomas. Since rat Muc4 was shown to interact with ErbB-2 tyrosine kinase receptor and to either promote cell survival and differentiation or cell proliferation, it is postulated that MUC4 may also participate in pancreatic carcinogenesis. Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells. Two MUC4-expressing WD (well-differentiated) (CAPAN-1 and -2) and one MUC4-non-expressing poorly differentiated (PANC-1) cell lines were used. The three cell lines express ErbB-2 at different levels. By co-transfection and site-directed mutagenesis, we show that PEA3 is a transactivator of the MUC4 promoter and that the -216 and -2368 PEA3 binding sites of the MUC4 promoter are essential. We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells. These results suggest that MUC4 is a new target gene of the Ets factor PEA3 in pancreatic cancer cells. In contrast, PEA3 represses the transcriptional activity of two fragments of the ErbB-2 promoter in a dose-dependent manner and decreases the endogenous ErbB-2 mRNA levels in WD cell lines. Thus, PEA3, by its capacity to up-regulate the epithelial marker MUC4 and to down-regulate the ErbB-2 oncogene, appears as a key regulator of the differentiation/proliferation balance in pancreatic cancer cells.
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MESH Headings
- Binding Sites
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Differentiation
- Cell Line, Tumor/metabolism
- Down-Regulation
- Gene Expression Regulation, Neoplastic/physiology
- Genes, erbB-2
- Humans
- Mucin-4
- Mucins
- Mutagenesis, Site-Directed
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Promoter Regions, Genetic
- Protein Interaction Mapping
- Proto-Oncogene Proteins c-jun/physiology
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Receptor, ErbB-2
- Sp1 Transcription Factor/physiology
- Structure-Activity Relationship
- Transcription Factors
- Transcriptional Activation
- Up-Regulation
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Affiliation(s)
| | - Michael Perrais
- *Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
| | - Sylvain Cerulis
- *Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
| | | | | | | | - Pascal Pigny
- *Unité INSERM 560, Place de Verdun, 59045 Lille cedex, France
- †Université de Lille 2, Faculté de Médecine, 59045 Lille cedex, France
- To whom correspondence should be addressed (email .)
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Ding Y, Huang D, Chen XG. Development of an enzyme-linked immunosorbent assay (ELISA) for the specific detection of MEKK1 expression in cells. J Pharmacol Toxicol Methods 2005; 51:159-67. [PMID: 15767210 DOI: 10.1016/j.vascn.2004.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2004] [Accepted: 08/31/2004] [Indexed: 11/25/2022]
Abstract
INTRODUCTION MEKK1 is a 196-kDa serine-threonine kinase activated in response to a variety of stimuli, including EGF, lysophosphatidic acid, osmotic stress, UV light, and microtubule toxins. However, there are few reports about the expression level of MEKK1 in cancers. METHODS In this report, a direct competitive ELISA to quantify total MEKK1 in cell lines was developed. RESULTS The procedure showed a high sensitivity (detection limit: 0.17 ng/ml), good precision (coefficient of variation </=10.12) and acceptable linearity over a large range of MEKK1 concentrations (0.1-10,000 ng/ml). In a pilot study, this assay was used to quantify MEKK1 in different cell lines. In cancer cells, the range of MEKK1 is 0.02-85 ng/mg protein and its concentration was higher in pancreas cancer cells and umbilical vein cells than that in others. DISCUSSION This method can be used to measure the MEKK1 level of cell samples. The activity of MEKK1/JNK pathway in pancreas cancer and umbilical vein cell lines indicates that MEKK1 may be a potential target in interfering with pancreas cancer and angiogenesis.
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Affiliation(s)
- Yan Ding
- Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xian Nong Tan Street, Beijing 100050, China
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Bian D, Su S, Mahanivong C, Cheng RK, Han Q, Pan ZK, Sun P, Huang S. Lysophosphatidic Acid Stimulates Ovarian Cancer Cell Migration via a Ras-MEK Kinase 1 Pathway. Cancer Res 2004; 64:4209-17. [PMID: 15205333 DOI: 10.1158/0008-5472.can-04-0060] [Citation(s) in RCA: 103] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Lysophosphatidic acid (LPA) is present at high concentrations in ascites and plasma of ovarian cancer patients. Studies conducted in experimental models demonstrate that LPA promotes ovarian cancer invasion/metastasis by up-regulating protease expression, elevating protease activity, and enhancing angiogenic factor expression. In this study, we investigated the effect of LPA on ovarian cancer migration, an essential component of cancer cell invasion. LPA stimulates both chemotaxis and chemokinesis of ovarian cancer cells and LPA-stimulated cell migration is G(I) dependent. Moreover, constitutively active H-Ras enhances ovarian cancer cell migration, whereas dominant negative H-Ras blocks LPA-stimulated cell migration, suggesting that Ras works downstream of G(i) to mediate LPA-stimulated cell migration. Interestingly, H-Ras mutants that specifically activate Raf-1, Ral-GDS, or phosphatidylinositol 3'-kinase are unable to significantly enhance ovarian cancer cell migration, suggesting that a Ras downstream effector distinct from Raf-1, Ral-GDS, and phosphatidylinositol 3'-kinase is responsible for LPA-stimulated cell migration. In this article, we demonstrate that LPA activates mitogen-activated protein kinase kinase 1 (MEKK1) in a G(i)-Ras-dependent manner and that MEKK1 activity is essential for LPA-stimulated ovarian cancer cell migration. Inhibitors that block MEKK1 downstream pathways, including MEK1/2, MKK4/7, and nuclear factor-kappa B pathways, do not significantly alter LPA-stimulated cell migration. Instead, LPA induces the redistribution of focal adhesion kinase to focal contact regions of the cytoplasm membrane, and this event is abolished by pertussis toxin, dominant negative H-Ras, or dominant negative MEKK1. Our studies thus suggest that the G(i)-Ras-MEKK1 signaling pathway mediates LPA-stimulated ovarian cancer cell migration by facilitating focal adhesion kinase redistribution to focal contacts.
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Affiliation(s)
- Dafang Bian
- Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
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Munshi A, Kurland JF, Nishikawa T, Chiao PJ, Andreeff M, Meyn RE. Inhibition of constitutively activated nuclear factor-κB radiosensitizes human melanoma cells. Mol Cancer Ther 2004. [DOI: 10.1158/1535-7163.985.3.8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Abstract
Melanoma tumors and cultured cell lines are relatively resistant to the cytotoxic effects of ionizing radiation, thereby limiting the use of radiotherapy for the clinical treatment of melanoma. New strategies for sensitizing melanoma cells therefore deserve examination. In an attempt to identify and target signaling pathways that contribute to radioresistance, we investigated the role of nuclear factor-κB (NF-κB), a transcription factor known to inhibit apoptosis induced by a variety of stimuli and promote radioresistance. Two human metastatic melanoma cell lines, A375 and MeWo, were used to examine the radiosensitizing effects of inhibitors of the NF-κB pathway. Nuclear extracts from these cell lines were tested for active NF-κB using the electrophoretic mobility shift assay. Both melanoma cell lines had constitutively activated NF-κB as observed by electrophoretic mobility shift assay. In an attempt to reverse NF-κB activity, cells were treated either with vehicle alone (DMSO) or with a proteasome inhibitor Z-Leu-Leu-Leu-H (MG132; 10 μmol/L for 2 hours prior to irradiation) that inhibited both constitutive and radiation-induced NF-κB activity. The clonogenic cell survival assay showed that pretreatment with MG132 enhanced tumor cell radiosensitivity with the survival factor at 2 Gy being reduced from 48 ± 0.8% and 48 ± 1.6% in vehicle-treated cells to 27.7 ± 0.32% and 34.3 ± 0.7% in MG132-treated MeWo and A375 cells, respectively. To test the role of NF-κB in radioresistance more directly, MeWo cells were stably transfected with a dominant-negative mutant IκBα construct, which led to the inhibition of both constitutive and radiation-induced NF-κB activity. A modest restoration of radiosensitivity was also observed in the stably transfected MeWo cells with survival factor at 2 Gy values being reduced from 47 ± 0.8% in parental MeWo cells to 32.9 ± 0.7% in stable transfectants. Because constitutively activated mitogen-activated protein kinase kinase (MEK) pathway has been shown to lead to activated NF-κB, we wanted to determine the relative contribution of activated MEK in the human melanoma cells. To test this, MeWo and A375 melanoma cells were exposed to the MEK inhibitor PD184352. Treatment with PD184352 partially reversed NF-κB activity but did not impart radiation sensitivity to these cells. Our results indicate that activated NF-κB may be one of the pathways responsible for the radioresistance of melanoma cells and that strategies for inhibiting its influence may be useful in restoring the radioresponse of melanomas.
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Affiliation(s)
| | | | | | | | - Michael Andreeff
- 3Blood and Marrow Transplantation, University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K. Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 2004; 64:2030-8. [PMID: 15026340 DOI: 10.1158/0008-5472.can-03-1945] [Citation(s) in RCA: 186] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The aggressive biology of human pancreatic adenocarcinoma has been linked with overexpression of vascular endothelial growth factor (VEGF). Constitutive activation of the transcription factor Sp1 plays a critical role in VEGF overexpression. Recent studies indicated that celecoxib, a selective cyclooxygenase-2 inhibitor, exhibits potent antitumor activity. However, the underlying molecular mechanisms of this activity remain unclear. In the present study, we used a pancreatic cancer model to determine the role of Sp1 in the antitumor activity of celecoxib. Treatment of various pancreatic cancer cells with celecoxib suppressed VEGF expression at both the mRNA and protein level in a dose-dependent manner. VEGF promoter deletion and point mutation analyses indicated that a region between nucleotide -109 and -61 and its intact Sp1-binding sites were required for the inhibition of VEGF promoter activity by celecoxib. Also, celecoxib treatment reduced both Sp1 DNA binding activity and transactivating activity. This decreased activity correlated with reduced Sp1 protein and its phosphorylation as determined using Western blot analysis. Furthermore, in an orthotopic pancreatic cancer animal model, celecoxib treatment inhibited tumor growth and metastasis. The antitumor activity was consistent with inhibition of angiogenesis as determined by evaluating tumor microvessel formation, which correlated with decreased Sp1 activity and VEGF expression. Collectively, our data provide a novel molecular mechanism for the antitumor activity of celecoxib and may help further improve its effectiveness in controlling pancreatic cancer growth and metastasis.
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Affiliation(s)
- Daoyan Wei
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
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Nawata R, Yujiri T, Nakamura Y, Ariyoshi K, Takahashi T, Sato Y, Oka Y, Tanizawa Y. MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-κB activation. Oncogene 2003; 22:7774-80. [PMID: 14586403 DOI: 10.1038/sj.onc.1206901] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Bcr-Abl tyrosine kinase, a chimeric oncoprotein responsible for chronic myelogenous leukemia, constitutively activates several signal transduction pathways that stimulate cell proliferation and prevent apoptosis in hematopoietic cells. The antiapoptotic function of Bcr-Abl is necessary for hematopoietic transformation, and also contributes to leukemogenesis. Herein, we show for the first time that cell transformation induced by Bcr-Abl leads to increased expression and kinase activity of MEK kinase 1 (MEKK1), which acts upstream of the c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and NF-kappaB signaling pathways. Inhibition of MEKK1 activity using a dominant-negative MEKK1 mutant (MEKK1km) diminished the ability of Bcr-Abl to protect cells from genotoxin-induced apoptosis, but had no effect on the proliferation of Bcr-Abl-transformed cells. Expression of MEKK1km also reduced NF-kappaB activation, and inhibited antiapoptotic c-IAP1 and c-IAP2 mRNA expression in response to the genotoxin. By contrast, neither JNK nor ERK activation was affected. These results indicate that MEKK1 is a downstream target of Bcr-Abl, and that the antiapoptotic effect of Bcr-Abl in chronic myelogenous leukemia cells is mediated via the MEKK1-NF-kappaB pathway.
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Affiliation(s)
- Ryouhei Nawata
- Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi 755-8505, Japan
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Kurland JF, Voehringer DW, Meyn RE. The MEK/ERK pathway acts upstream of NF kappa B1 (p50) homodimer activity and Bcl-2 expression in a murine B-cell lymphoma cell line. MEK inhibition restores radiation-induced apoptosis. J Biol Chem 2003; 278:32465-70. [PMID: 12801933 DOI: 10.1074/jbc.m212919200] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
In a previously published report (Kurland, J. F., Kodym, R., Story, M. D., Spurgers, K. B., McDonnell, T. J., and Meyn, R. E. (2001) J. Biol. Chem. 276, 45380-45386), we described the NF kappa B status for two murine B-cell lymphoma cell lines, LY-as (apoptosis-sensitive) and LY-ar (apoptosis-refractory) and provided evidence that NF kappa B1 (p50) homodimers contribute to the expression of Bcl-2 in the LY-ar line. In the present study, we investigated the upstream signals leading to p50 homodimer activation and Bcl-2 expression. We found that in LY-ar cells, ERK1 and ERK2 were constitutively phosphorylated, whereas LY-as cells had no detectable ERK1 or ERK2 phosphorylation. Treatment of LY-ar cells with the MEK inhibitors PD 98059, U0126, and PD 184352 led to a loss of phosphorylated ERK1 and ERK2, a reversal of nuclear p50 homodimer DNA binding, and a decrease in Bcl-2 protein expression. Similarly, activation of the MEK/ERK pathway in LY-as cells by phorbol ester led to Bcl-2 expression that could be blocked by PD 98059. Furthermore, treatment of LY-ar cells with tumor necrosis factor-alpha, an I kappa B kinase activator, did not alter the suppressive effect of PD 98059 on p50 homodimer activity, suggesting an I kappa B kinase-independent pathway for p50 homodimer activation. Lastly, all three MEK inhibitors sensitized LY-ar cells to radiation-induced apoptosis. We conclude that the MEK/ERK pathway acts upstream of p50 homodimer activity and Bcl-2 expression in this B-cell lymphoma cell system and suggest that the use of MEK inhibitors could be useful clinically in combination with ionizing radiation to treat lymphoid malignancies.
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Affiliation(s)
- John F Kurland
- Department of Experimental Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
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