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Abdelatty A, Fang D, Wei G, Wu F, Zhang C, Xu H, Yao C, Wang Y, Xia H. PKCι Is a Promising Prognosis Biomarker and Therapeutic Target for Pancreatic Cancer. Pathobiology 2022; 89:370-381. [PMID: 35785767 DOI: 10.1159/000521588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/13/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND As the highest prevalent pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) ranks the 7th lethal malignancy worldwide. The late diagnosis, chemotherapeutic resistance, and high associated mortality make PDAC a dilemma facing the oncologists. Protein kinase C (PKC) enzymes have been shown to be important in different cancer progression. METHODS To understand the pattern of PKC enzymes in PDAC, we examined all PKC family member genes expression in PDAC and matched normal tissues. The critical role of PKCι was further investigated in different PDAC cells using cellular and molecular technology. RESULTS We found that PRKCI (PKCι) was the most significantly overexpressed PKCs in pancreatic cancer. However, little is known about its role and regulation of oncogenic signaling pathways in pancreatic cancer. In this study, we confirmed the overexpression of PKCι in PDAC, and this high expression was associated with poor prognosis of patients. We proved that knockdown of PKCι by small interfering RNA or shRNA significantly inhibited pancreatic cancer cell growth and migration or invasion. Conversely, PKCι overexpression promoted pancreatic cancer cell growth and migration. Moreover, bioinformatical and technical studies informed the participation of PKCι in regression of apoptosis in PDAC cells, which may be related to the regulation of both PI3K/AKT and Wnt/β-catenin pathways. CONCLUSIONS Therefore, our results are adding more insight into the importance of PKCι in pancreatic cancer. PKCι induces pancreatic cancer progression through activation of PI3K/AKT and Wnt/β-catenin signaling pathways, which may provide a promising therapeutic target for pancreatic cancer.
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Affiliation(s)
- Alaa Abdelatty
- Department of Pathology in the School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
- Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wannan Medical College, Wuhu, China
- Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt
| | - Dan Fang
- Department of Pathology in the School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Guanqun Wei
- Department of Pathology in the School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Fubing Wu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Chengfei Zhang
- Department of Pathology in the School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Haojun Xu
- Department of Pathology in the School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
| | - Chengyun Yao
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Yundong Wang
- Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Nanjing, China
| | - Hongping Xia
- Department of Gastroenterology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wannan Medical College, Wuhu, China
- Department of Pathology in the School of Basic Medical Sciences, Key Laboratory of Antibody Technique of National Health Commission, Jiangsu Antibody Drug Engineering Research Center, Nanjing Medical University, Nanjing, China
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
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Nisar S, Hashem S, Macha MA, Yadav SK, Muralitharan S, Therachiyil L, Sageena G, Al-Naemi H, Haris M, Bhat AA. Exploring Dysregulated Signaling Pathways in Cancer. Curr Pharm Des 2020; 26:429-445. [PMID: 31939726 DOI: 10.2174/1381612826666200115095937] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 11/27/2019] [Indexed: 02/08/2023]
Abstract
Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.
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Affiliation(s)
- Sabah Nisar
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Sheema Hashem
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Muzafar A Macha
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States.,Department of Biotechnology, Central University of Kashmir, Ganderbal, Jammu and Kashmir, India
| | - Santosh K Yadav
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | | | - Lubna Therachiyil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | | | - Hamda Al-Naemi
- Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Mohammad Haris
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Ajaz A Bhat
- Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
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Kaur A, Riaz MS, Murugaiah V, Varghese PM, Singh SK, Kishore U. A Recombinant Fragment of Human Surfactant Protein D induces Apoptosis in Pancreatic Cancer Cell Lines via Fas-Mediated Pathway. Front Immunol 2018; 9:1126. [PMID: 29915574 PMCID: PMC5994421 DOI: 10.3389/fimmu.2018.01126] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 05/03/2018] [Indexed: 12/24/2022] Open
Abstract
Human surfactant protein D (SP-D) is a potent innate immune molecule, which is emerging as a key molecule in the recognition and clearance of altered and non-self targets. Previous studies have shown that a recombinant fragment of human SP-D (rfhSP-D) induced apoptosis via p53-mediated apoptosis pathway in an eosinophilic leukemic cell line, AML14.3D10. Here, we report the ability of rfhSP-D to induce apoptosis via TNF-α/Fas-mediated pathway regardless of the p53 status in human pancreatic adenocarcinoma using Panc-1 (p53mt), MiaPaCa-2 (p53mt), and Capan-2 (p53wt) cell lines. Treatment of these cell lines with rfhSP-D for 24 h caused growth arrest in G1 cell cycle phase and triggered transcriptional upregulation of pro-apoptotic factors such as TNF-α and NF-κB. Translocation of NF-κB from the cytoplasm into the nucleus of pancreatic cancer cell lines was observed via immunofluorescence microscopy following treatment with rfhSP-D as compared to the untreated cells. The rfhSP-D treatment caused upregulation of pro-apoptotic marker Fas, as analyzed via qPCR and western blot, which then triggered caspase cascade, as evident from cleavage of caspase 8 and 3 analyzed via western blot at 48 h. The cell number following the rfhSP-D treatment was reduced in the order of Panc-1 (~67%) > MiaPaCa-2 (~60%) > Capan-2 (~35%). This study appears to suggest that rfhSP-D can potentially be used to therapeutically target pancreatic cancer cells irrespective of their p53 phenotype.
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Affiliation(s)
- Anuvinder Kaur
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Muhammad Suleman Riaz
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Valarmathy Murugaiah
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Praveen Mathews Varghese
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Shiv K. Singh
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, Goettingen, Germany
| | - Uday Kishore
- Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
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Lewinska A, Adamczyk-Grochala J, Deregowska A, Wnuk M. Sulforaphane-Induced Cell Cycle Arrest and Senescence are accompanied by DNA Hypomethylation and Changes in microRNA Profile in Breast Cancer Cells. Theranostics 2017; 7:3461-3477. [PMID: 28912888 PMCID: PMC5596436 DOI: 10.7150/thno.20657] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 05/29/2017] [Indexed: 12/21/2022] Open
Abstract
Cancer cells are characterized by genetic and epigenetic alterations and phytochemicals, epigenetic modulators, are considered as promising candidates for epigenetic therapy of cancer. In the present study, we have investigated cancer cell fates upon stimulation of breast cancer cells (MCF-7, MDA-MB-231, SK-BR-3) with low doses of sulforaphane (SFN), an isothiocyanate. SFN (5-10 µM) promoted cell cycle arrest, elevation in the levels of p21 and p27 and cellular senescence, whereas at the concentration of 20 µM, apoptosis was induced. The effects were accompanied by nitro-oxidative stress, genotoxicity and diminished AKT signaling. Moreover, SFN stimulated energy stress as judged by decreased pools of ATP and AMPK activation, and autophagy induction. Anticancer effects of SFN were mediated by global DNA hypomethylation, decreased levels of DNA methyltransferases (DNMT1, DNMT3B) and diminished pools of N6-methyladenosine (m6A) RNA methylation. SFN (10 µM) also affected microRNA profiles, namely SFN caused upregulation of sixty microRNAs and downregulation of thirty two microRNAs, and SFN promoted statistically significant decrease in the levels of miR-23b, miR-92b, miR-381 and miR-382 in three breast cancer cells. Taken together, we show for the first time that SFN is an epigenetic modulator in breast cancer cells that results in cell cycle arrest and senescence, and SFN may be considered to be used in epigenome-focused anticancer therapy.
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Affiliation(s)
- Anna Lewinska
- Laboratory of Cell Biology, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland
| | | | - Anna Deregowska
- Department of Genetics, University of Rzeszow, Kolbuszowa, Poland
- Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Maciej Wnuk
- Department of Genetics, University of Rzeszow, Kolbuszowa, Poland
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Shimura T, Kofunato Y, Okada R, Yashima R, Okada K, Araki K, Hosouchi Y, Kuwano H, Takenoshita S. MIB-1 labeling index, Ki-67, is an indicator of invasive intraductal papillary mucinous neoplasm. Mol Clin Oncol 2016; 5:317-322. [PMID: 27446570 DOI: 10.3892/mco.2016.908] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 05/09/2016] [Indexed: 01/25/2023] Open
Abstract
Despite strict criteria for the observation of intraductal papillary mucinous neoplasm (IPMN), it remains difficult to distinguish invasive IPMN from non-invasive IPMN. The aim of the present study was to identify an indicator of invasive IPMN. The present study retrospectively evaluated 53 patients (28 with non-invasive and 25 with invasive IPMN) who underwent resection of IPMN, and examined the usefulness of the MIB-1 labeling index as an indicator of invasive IPMN. The MIB-1 labeling indexes in patients with invasive IPMN were significantly higher compared with those with non-invasive IPMN (P<0.001). A receiver operating characteristic curve revealed that the area under the curve was 0.822. These results suggested that a cut-off level for the MIB-1 labeling index should be set to 15.5% to distinguish invasive from non-invasive IPMN. A multivariate analysis using a logistic regression model revealed the MIB-1 labeling index (hazard ratio, 18.692; 95% confidential interval, 4.171-83.760; P<0.001) and the existence of mural nodules (hazard ratio, 6.187, 95% confidential interval, 1.039-36.861; P=0.045) were predictive factors for invasive IPMN. However, no statistically significant differences were observed between patients with a lower MIB-1 labeling index and patients with a higher MIB-1 labeling index (P=0.798). The MIB-1 labeling index must be considered as a candidate for the classification of IPMN.
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Affiliation(s)
- Tatsuo Shimura
- Department of Cancer Biology and Electronics, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Yasuhide Kofunato
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Ryo Okada
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Rei Yashima
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
| | - Koji Okada
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Kenichiro Araki
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Yasuo Hosouchi
- Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Gunma 371-0821, Japan
| | - Hiroyuki Kuwano
- Department of General Surgical Science, Gunma University Graduate School of Medicine, Gunma 371-8511, Japan
| | - Seiichi Takenoshita
- Department of Organ Regulatory Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
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Birtolo C, Go VLW, Ptasznik A, Eibl G, Pandol SJ. Phosphatidylinositol 3-Kinase: A Link Between Inflammation and Pancreatic Cancer. Pancreas 2016; 45:21-31. [PMID: 26658038 PMCID: PMC4859755 DOI: 10.1097/mpa.0000000000000531] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Even though a strong association between inflammation and cancer has been widely accepted, the underlying precise molecular mechanisms are still largely unknown. A complex signaling network between tumor and stromal cells is responsible for the infiltration of inflammatory cells into the cancer microenvironment. Tumor stromal cells such as pancreatic stellate cells (PSCs) and immune cells create a microenvironment that protects cancer cells through a complex interaction, ultimately facilitating their local proliferation and their migration to different sites. Furthermore, PSCs have multiple functions related to local immunity, angiogenesis, inflammation, and fibrosis. Recently, many studies have shown that members of the phosphoinositol-3-phosphate kinase (PI3K) family are activated in tumor cells, PSCs, and tumor-infiltrating inflammatory cells to promote cancer growth. Proinflammatory cytokines and chemokines secreted by immune cells and fibroblasts within the tumor environment can activate the PI3K pathway both in cancer and inflammatory cells. In this review, we focus on the central role of the PI3K pathway in regulating the cross talk between immune/stromal cells and cancer cells. Understanding the role of the PI3K pathway in the development of chronic pancreatitis and cancer is crucial for the discovery of novel and efficacious treatment options.
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Affiliation(s)
- Chiara Birtolo
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA,Department of Internal Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Italy
| | - Vay Liang W. Go
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Andrzej Ptasznik
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Stephen J. Pandol
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA,VA Greater Los Angeles Health Care System, Los Angeles, CA
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Nagaraju GP, Mezina A, Shaib WL, Landry J, El-Rayes BF. Targeting the Janus-activated kinase-2-STAT3 signalling pathway in pancreatic cancer using the HSP90 inhibitor ganetespib. Eur J Cancer 2015; 52:109-19. [PMID: 26682870 DOI: 10.1016/j.ejca.2015.10.057] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 10/06/2015] [Accepted: 10/23/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is an aggressive malignancy characterised by chemoresistance. HSP90 is important for stabilisation of proteins, cell signalling and malignant growth. We hypothesised that ganetespib, an HSP90 inhibitor, can inhibit PC cell growth by interfering with multiple signalling cascades, including the Janus-activated kinase (JAK)-STAT pathway, and act synergistically with chemotherapeutic drugs. METHODS The effects of ganetespib were evaluated in ASPC-1, HPAC, MIA PaCA-2 and PANC-1 cell lines using a cell proliferation assay. Effects on the expression of phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK) and JAK-STAT pathways were examined by Western blot. JAK2 and STAT3 were knocked down by transient transfection with JAK2 or STAT3 small interfering RNA. ASPC-1 and HPAC cell lines were tested for sensitivity to ganetespib, 5-fluorouracil/oxaliplatin, and gemcitabine/paclitaxel, alone and in combination, using an in vivo tumour xenograft model. RESULTS Ganetespib significantly decreased cell proliferation in all tested PC cell lines. Ganetespib decreased the activation of extracellular signal-related kinase (ERK), PI3K/AKT, and c-Jun NH2-terminal kinase (JNK) signalling molecules and diminished the activation of STAT3 in an additive manner with isolated downregulation of JAK2 expression. In animal models, ganetespib potentiated the effects of 5-fluouracil/oxaliplatin and gemcitabine/paclitaxel, as measured by tumour volume. Western blot analysis from tumours removed from animals confirmed the effects of ganetespib on PI3K/AKT, ERK and JNK pathways. CONCLUSIONS Ganetespib inhibits the growth of PC cells, an effect associated with downregulation of signalling through the JAK2-STAT3, PI3K/AKT and MAPK pathways. This provides preclinical proof-of-principle that ganetespib enhances the activity of chemotherapeutic agents and warrants further evaluation in PC clinical trials.
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Affiliation(s)
| | - Anya Mezina
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Walid L Shaib
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Jerome Landry
- Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.
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Bai G, Wu C, Gao Y, Shu G. Exploring the Functional Disorder and Corresponding Key Transcription Factors in Intraductal Papillary Mucinous Neoplasms Progression. Int J Genomics 2015; 2015:197603. [PMID: 26425543 PMCID: PMC4573622 DOI: 10.1155/2015/197603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 08/11/2015] [Indexed: 12/18/2022] Open
Abstract
This study has analyzed the gene expression patterns of an IPMN microarray dataset including normal pancreatic ductal tissue (NT), intraductal papillary mucinous adenoma (IPMA), intraductal papillary mucinous carcinoma (IPMC), and invasive ductal carcinoma (IDC) samples. And eight clusters of differentially expressed genes (DEGs) with similar expression pattern were detected by k-means clustering. Then a survey map of functional disorder in IPMN progression was established by functional enrichment analysis of these clusters. In addition, transcription factors (TFs) enrichment analysis was used to detect the key TFs in each cluster of DEGs, and three TFs (FLI1, ERG, and ESR1) were found to significantly regulate DEGs in cluster 1, and expression of these three TFs was validated by qRT-PCR. All these results indicated that these three TFs might play key roles in the early stages of IPMN progression.
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Affiliation(s)
- Guiying Bai
- Department of Oncology, Tianjin Third Central Hospital, Tianjin 300179, China
- Key Laboratory of Artificial Cell Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin 300179, China
| | - Chenxuan Wu
- Department of Oncology, Tianjin Third Central Hospital, Tianjin 300179, China
| | - Yingtang Gao
- Key Laboratory of Artificial Cell Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin 300179, China
| | - Guiming Shu
- Department of Hepatobiliary Surgery, Tianjin Third Central Hospital, Tianjin 300179, China
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Pedersen KS, Kim GP, Foster NR, Wang-Gillam A, Erlichman C, McWilliams RR. Phase II trial of gemcitabine and tanespimycin (17AAG) in metastatic pancreatic cancer: a Mayo Clinic Phase II Consortium study. Invest New Drugs 2015; 33:963-8. [PMID: 25952464 DOI: 10.1007/s10637-015-0246-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 04/28/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Heat Shock Protein 90 (HSP90) is a molecular chaperone that stabilizes many oncogenic proteins. HSP90 inhibitors may sensitize tumors to cytotoxic agents by causing client protein degradation. Gemcitabine, which has modest activity in pancreas cancer, activates Chk1, a client protein of HSP90. This phase II trial was designed to determine whether 17AAG could enhance the clinical activity of gemcitabine through degradation of Chk1 in patients with stage IV pancreatic cancer. METHODS A multicenter, prospective study combining gemcitabine and 17AAG enrolled patients with stage IV pancreatic adenocarcinoma, adequate liver and kidney function, ECOG performance status 0-2, and no prior chemotherapy for metastatic disease. The primary goal was to achieve a 60 % overall survival at 6 months. Sixty-six patients were planned for accrual, with an interim analysis after 25 patients enrolled. RESULTS After a futility analysis to achieve the endpoint, accrual was halted with 21 patients enrolled. No complete or partial responses were seen. Forty percent of patients were alive at 6 months. Median overall survival was 5.4 months. Tolerability was moderate, with 65 % of patients having ≥ grade 3 adverse events (AE), and 15 % having grade 4 events. CONCLUSIONS The lack of clinical activity suggests that targeting Chk1 by inhibiting HSP90 is not important in pancreatic cancer sensitivity to gemcitabine alone. Further studies of HSP90 targeted agents with gemcitabine alone are not warranted.
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Johnson B, Mahadevan D. Emerging Role and Targeting of Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACAM6) in Human Malignancies. CLINICAL CANCER DRUGS 2015; 2:100-111. [PMID: 27595061 PMCID: PMC4997943 DOI: 10.2174/2212697x02666150602215823] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 04/30/2015] [Accepted: 06/30/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of the CEA family of cell adhesion proteins that belong to the immunoglobulin superfamily. CEACAM6 is normally expressed on the surface of myeloid (CD66c) and epithelial surfaces. Stiochiomertic expression of members of the CEA family (CEACAM1, 5, 6, 7) on epithelia maintains normal tissue architecture through homo-and hetero-philic interactions. Dysregulated over-expression of CEACAM6 is oncogenic, is associated with anoikis resistance and an invasive phenotype mediated by excessive TGFβ, AKT, FAK and SRC signaling in human malignancies. METHODS Extensive literature review through PubMed was conducted to identify relevant preclinical and clinical research publications regarding CEACAM6 over the last decade and was summarized in this manuscript. RESULTS CEACAM5 and 6 are over-expressed in nearly 70% of epithelial malignancies including colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDA), hepatobiliary, gastric, breast, non-small cell lung and head/neck cancers. Importantly, CEACAM6 is a poor prognostic marker in CRC, while its expression correlates with tumor stage, metastasis and post-operative survival in PDA. CEACAM6 appears to be an immune checkpoint suppressor in hematologic malignancies including acute lymphoblastic leukemia and multiple myeloma. Several therapeutic monoclonal antibodies or antibody fragments targeting CEACAM6 have been designed and developed as a targeted therapy for human malignancies. A Llama antibody targeting CEACAM6 is being evaluated in early phase clinical trials. CONCLUSION This review focuses on the role of CEACAM6 in the pathogenesis and signaling of the malignant phenotype in solid and hematologic malignancies and highlights its potential as a therapeutic target for anti-cancer therapy.
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Affiliation(s)
- Benny Johnson
- The University of Tennessee Health Science Center & West Cancer Center, Memphis, TN,USA
| | - Daruka Mahadevan
- The University of Tennessee Health Science Center & West Cancer Center, Memphis, TN,USA
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11
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Ishikawa D, Shimada M, Utsunomiya T, Morine Y, Imura S, Ikemoto T, Arakawa Y, Kanamoto M, Iwahashi S, Saito Y, Yamada S, Miyake H. Effect of Twist and Bmi1 on intraductal papillary mucinous neoplasm of the pancreas. J Gastroenterol Hepatol 2014; 29:2032-7. [PMID: 24909638 DOI: 10.1111/jgh.12652] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Intraductal papillary mucinous neoplasm (IPMN) is a well-established entity among pancreatic neoplasms that ranges from low-grade dysplasia to invasive carcinoma. Epithelial-mesenchymal transition (EMT) contributes to tumor progression in various cancers. Moreover, Notch signaling is one of the important upstream effectors of EMT promotion. Currently, it is unclear whether EMT causes pathological progression of IPMN. AIM We evaluated the expression of EMT-promoting transcription factors Twist and B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1) in IPMN. METHODS Patients who underwent resections at our institute and its affiliated hospital were enrolled in this study (n = 35). Protein expression of EMT markers Twist, Bmi1, Jagged1, and E-cadherin in resected specimens was investigated by immunohistochemistry. Expression of these proteins was compared with the clinicopathological factors and patient survival. RESULTS Positive expression of Twist and Bmi1 was observed in 40.0% and 42.9% of IPMNs, respectively. Twist and Bmi1 expression was significantly higher in IPMNs with high-grade dysplasia (P < 0.05) and invasive carcinoma (P < 0.05) than that in IPMNs with low-grade dysplasia. High expression of Twist was correlated with Jagged1 expression and inversely correlated with expression of E-cadherin (P = 0.06 and P < 0.05, respectively). In survival analyses, the recurrence rate was significantly higher in the group that showed simultaneous high expression of Twist and Bmi1 (P < 0.05). CONCLUSIONS Expression of Twist and Bmi1 is associated with aggressiveness and poor prognoses of IPMN through EMT promotion that might be induced by Notch signaling.
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Affiliation(s)
- Daichi Ishikawa
- Department of Surgery, The University of Tokushima, Tokushima, Japan
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Akt and p53R2, partners that dictate the progression and invasiveness of cancer. DNA Repair (Amst) 2014; 22:24-9. [PMID: 25086499 DOI: 10.1016/j.dnarep.2014.07.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Accepted: 07/01/2014] [Indexed: 01/25/2023]
Abstract
The serine/threonine kinase or the so-called "Akt" is a key regulatory molecule of signaling pathway that regulates various cellular processes. Many intracellular proteins are involved in the activation or inhibition of Akt signaling and the hyperactivation of Akt signaling pathway is found to be frequently involved in various types of human cancers. Furthermore, while p53R2, a p53-inducible peptide involved in the synthesis of dNTPs normally works toward suppression of cancer through elimination of reactive oxygen species (ROS), inhibition of MAPK/ERK pathway and providing dNTPs for DNA repair, the overexpression of p53R2 is reported to be associated with cancer progression and resistance to therapy. In this review article, we will discuss the situation in which cancer cells with hyperactive PI3K/Akt signaling can recruit p53R2 in favor of cancer progression and resistance to therapy. In the hyperactive state of PI3K/Akt signaling (which happens in the absence of deactivation or excess of activation), p53R2 can be used by cancer cells to promote proliferation. Therefore, the hyperactivity of PI3K/Akt pathway and elevated levels of p53R2 can give rise to highly invasive cancers.
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Chakraborty K, Ramsauer VP, Stone W, Krishnan K. Tocotrienols in Pancreatic Cancer Treatment and Prevention. Cancer 2014. [DOI: 10.1016/b978-0-12-405205-5.00024-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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14
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Matsubara S, Ding Q, Miyazaki Y, Kuwahata T, Tsukasa K, Takao S. mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Sci Rep 2013; 3:3230. [PMID: 24231729 PMCID: PMC3828572 DOI: 10.1038/srep03230] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 10/31/2013] [Indexed: 12/23/2022] Open
Abstract
Pancreatic cancer is characterized by near-universal mutations in KRAS. The mammalian target of rapamycin (mTOR), which functions downstream of RAS, has divergent effects on stem cells. In the present study, we investigated the significance of the mTOR pathway in maintaining the properties of pancreatic cancer stem cells. The mTOR inhibitor, rapamycin, reduced the viability of CD133+ pancreatic cancer cells and sphere formation which is an index of self-renewal of stem-like cells, indicating that the mTOR pathway functions to maintain cancer stem-like cells. Further, rapamycin had different effects on CD133+ cells compared to cyclopamine which is an inhibitor of the Hedgehog pathway. Thus, the mTOR pathway has a distinct role although both pathways maintain pancreatic cancer stem cells. Therefore, mTOR might be a promising target to eliminate pancreatic cancer stem cells.
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Affiliation(s)
- Shyuichiro Matsubara
- Cancer and Regenerative Medicine, Frontier Biomedical Science and Swine Research Center, Sakuragaoka, Kagoshima, 890-8520, Japan
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Yee NS. Toward the goal of personalized therapy in pancreatic cancer by targeting the molecular phenotype. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2013; 779:91-143. [PMID: 23288637 DOI: 10.1007/978-1-4614-6176-0_5] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The purpose of this article is to provide a critical review of the molecular alterations in pancreatic cancer that are clinically investigated as therapeutic targets and their potential impact on clinical outcomes. Adenocarcinoma of exocrine pancreas is generally associated with poor prognosis and the conventional therapies are marginally effective. Advances in understanding the genetic regulation of normal and neoplastic development of pancreas have led to development and clinical evaluation of new therapeutic strategies that target the signaling pathways and molecular alterations in pancreatic cancer. Applications have begun to utilize the genetic targets as biomarkers for prediction of therapeutic responses and selection of treatment options. The goal of accomplishing personalized tumor-specific therapy with tolerable side effects for patients with pancreatic cancer is hopefully within reach in the foreseeable future.
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Affiliation(s)
- Nelson S Yee
- Division of Hematology-Oncology, Department of Medicine, Penn State College of Medicine, Penn State Hershey Cancer Institute, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033-0850, USA.
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16
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Ye B, Jiang LL, Xu HT, Zhou DW, Li ZS. Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol 2012; 25:627-36. [PMID: 23058013 DOI: 10.1177/039463201202500309] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway plays a crucial role in the formation and progression of many malignancies, and has been shown to be an important therapeutic target for cancer. In the present study, human gastric adenocarcinoma tissues of different grades (N=45) were collected. The protein expression of PI3Kp85α and phosphorylated AKT (p-AKT) was evaluated immunohistochemically in the biopsy samples. PI3K/AKT pathway was blocked by constructed recombinant small hairpin RNA adenovirus vector rAd5-PI3Kp85α (rAd5-P) used to transfect into human gastric cancer SGC-7901cell line. The transfection efficiency of rAd5-P in SGC-7901 cells was observed under fluorescent microscope. The expression of PI3Kp85α, p-AKT, Ki-67 and matrix metallopeptidase-2 (MMP-2) was detected by real-time PCR and Western blot assays. Cell proliferative activities and metastatic capabilities were determined by MTT and Transwell assays. As a consequence, the protein expression of PI3Kp85α and p-AKT was respectively observed in 80.0% and 82.2% gastric adenocarcinoma tissues, elevating with the ascending order of tumor malignancy. Targeted blockade of PI3K pathway decreased the expression of PI3Kp85α, p-AKT, Ki-67 and MMP-2, and inhibited the proliferative activities and metastatic capabilities of gastric cancer cells. In conclusion, PI3Kp85α and p-AKT were strongly expressed in gastric adenocarcinoma tissues, and targeted blockade of PI3K pathway may inhibit gastric cancer growth and metastasis through down-regulation of Ki-67 and MMP-2 expression. PI3K/AKT pathway may represent an important therapeutic target for gastric cancer.
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Affiliation(s)
- B Ye
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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17
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Xiao SY. Intraductal papillary mucinous neoplasm of the pancreas: an update. SCIENTIFICA 2012; 2012:893632. [PMID: 24278753 PMCID: PMC3820567 DOI: 10.6064/2012/893632] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 10/18/2012] [Indexed: 06/02/2023]
Abstract
Intraductal papillary mucinous neoplasm (IPMN) is a cystic tumor of the pancreas. The etiology is unknown, but increasing evidence suggests the involvement of several tumorigenesis pathways, including an association with hereditary syndromes. IPMN occurs more commonly in men, with the mean age at diagnosis between 64 and 67 years old. At the time of diagnosis, it may be benign, with or without dysplasia, or frankly malignant with an invasive carcinoma. Tumors arising from the main pancreatic duct are termed main-duct IPMNs, those involving the branch ducts, branch-duct IPMNs. In general, small branch-duct IPMNs are benign, particularly in asymptomatic patients, and can be safely followed. In contrast, main-duct tumors should be surgically resected and examined carefully for an invasive component. In the absence of invasion, patient's survival is excellent, from 94 to 100%. For patients with an IPMN-associated invasive carcinoma, the prognosis overall is better than those with a de novo pancreatic ductal adenocarcinoma, with a 5-year survival of 40% to 60% in some series. However, no survival advantage can be demonstrated if the invasive component in an IPMN patient is that of the conventional tubular type (versus mucinous carcinoma). Several histomorphologic variants are recognized, although the clinical significance of this "subtyping" is not well defined.
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Affiliation(s)
- Shu-Yuan Xiao
- Department of Pathology, University of Chicago Medical Center, 5841 South Maryland Avenue, MC6101, Chicago, IL 60637, USA
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Jiang P, Zang W, Wang L, Xu Y, Liu Y, Deng SX. Protein-protein interaction and SNP analysis in intraductal papillary mucinous neoplasm. Gene 2012; 513:219-24. [PMID: 23107772 DOI: 10.1016/j.gene.2012.10.047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 06/04/2012] [Accepted: 10/10/2012] [Indexed: 12/17/2022]
Abstract
Intraductal papillary mucinous neoplasm (IPMN) is a type of tumor that grows within the pancreatic ducts. It is a progress from hyperplasia to intraductal adenoma (IPMA), to noninvasive carcinoma, and ultimately to invasive carcinoma (IPMC). The objective of this study was to explore the molecular mechanism of the progression from IPMA to IPMC. By using the GSE19650 affymetrix microarray data accessible from Gene Expression Omnibus (GEO) database, we first identified the differentially expressed genes (DEGs) between IPMA and IPMC, followed by the protein-protein interaction and single-nucleotide polymorphism (SNP) analysis of the DEGs. Our study identified thousands of DEGs which involved regulation of cell cycle and apoptosis in this progression from IPMA to IPMC. Protein-protein interaction network construction found that MYC, IL6ST, NR3C1, CREBBP, GATA1 and LRP1 might play an important role in the progression. Furthermore, the SNP analysis confirmed the association between BRAC1 and pancreas cancer. In conclusion, our data provide a comprehensive bioinformatics analysis of genes and pathways which may be involved in the progression of IPMN from IPMA to IPMC.
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Affiliation(s)
- Pu Jiang
- Department of Forensic Medicine, College of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China
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Dong YD, Cui L, Peng CH, Cheng DF, Han BS, Huang F. Expression and clinical significance of HMGB1 in human liver cancer: Knockdown inhibits tumor growth and metastasis in vitro and in vivo. Oncol Rep 2012; 29:87-94. [PMID: 23042506 DOI: 10.3892/or.2012.2070] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 08/21/2012] [Indexed: 12/18/2022] Open
Abstract
The high-mobility group box 1 (HMGB1) signaling pathway plays a crucial role in tumorigenesis and progression of many malignant cancers. The present study aimed to investigate the expression and clinical significance of HMGB1 in human primary liver cancer, and further explore the molecular mechanisms of HMGB1 in tumor growth and metastasis. Forty cases of human liver cancer and normal liver tissues were collected. The expression of HMGB1 was assessed using RT-PCR and western blot assays in biopsy samples. The HMGB1 pathway in vitro was blocked using transfection of the recombinant small hairpin RNA adenovirus vector rAd5-HMGB1 into the human liver cancer cell line SMMC-7721. The expression of HMGB1, phosphorylated AKT (p-AKT), Ki-67 and matrix metallopeptidase-2 (MMP-2) was detected by Real-PCR and western blot assays. Cell proliferative activities and metastatic capability were determined by MTT and Transwell assays. Cell cycle distribution and apoptosis were detected by flow cytometry. A subcutaneous xenograft tumor model was established, validating the effects of rAd5-HMGB1 on tumor growth in vivo. As a consequence, HMGB1 was found to be highly expressed in liver cancer compared with normal tissues, and was positively associated with pathological grade and distant metastases of liver cancer. Knockdown of HMGB1 downregulated the expression of p-AKT, Ki-67 and MMP-2, inhibited the proliferative activities and metastatic potential of SMMC-7721 cells, induced cell cycle arrest and apoptosis, and slowed the growth of xenograft tumors. Altogether, the expression of HMGB1 is closely correlated with pathological grade and distant metastases of liver cancer, and knockdown of HMGB1 inhibits liver cancer growth and metastasis, suggesting that HMGB1 may be involved in liver cancer development and progression through AKT-mediated regulation of Ki-67 and MMP-2 expression, and represent a potential therapeutic target for this aggressive malignancy.
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Affiliation(s)
- Ya-Dong Dong
- Department of General Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China
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Iovanna J, Calvo EL, Dagorn JC, Dusetti N. Pancreatic Cancer Genetics. DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC VALUE OF GENE SIGNATURES 2012:51-79. [DOI: 10.1007/978-1-61779-358-5_5] [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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Clinicopathologic study of the MIB-1 labeling index (Ki67) and postoperative prognosis for intraductal papillary mucinous neoplasms and ordinary ductal adenocarcinoma. Pancreas 2012; 41:114-20. [PMID: 22143341 DOI: 10.1097/mpa.0b013e318220c1fa] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES Intraductal papillary mucinous neoplasms (IPMNs) are pathologically classified as IPMN with low- or intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. A stepwise carcinogenic pathway has been considered for IPMN. However, it is not obvious when surgical resection should be performed for IPMN. METHODS We studied the MIB-1 labeling index in cases of IPMN and ordinary ductal adenocarcinoma (ODA). Moreover, IPMN with an associated invasive carcinoma was divided into 2, namely, carcinoma in situ and invasive components, and the respective MIB-1 labeling indexes were examined. RESULTS The MIB-1 labeling index for IPMN with low- or intermediate-grade dysplasia (1.8%) was significantly lower than those for IPMN with high-grade dysplasia (14.2%), both the carcinoma in situ components (23.1%) and invasive components (19.2%) within the IPMN with an associated invasive carcinoma, and ODA (19.5%; P < 0.0001).The 5-year survival rates after resection were 100% for IPMN with low- or intermediate-grade dysplasia, 83.3% for IPMN with high-grade dysplasia, 53.8% for IPMN with an associated invasive carcinoma, and 10.3% for ODA. CONCLUSIONS MIB-1 might be useful for the classification of malignant potential in IPMN. Intraductal papillary mucinous neoplasm should be surgically resected when the tumor is diagnosed as IPMN with high-grade dysplasia.
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Ke XY, Wang Y, Xie ZQ, Liu ZQ, Zhao Q. LY294002 combined with gemcitabine inhibits p-Akt and MRP expression in human pancreatic carcinoma PANC-1 cells. Shijie Huaren Xiaohua Zazhi 2011; 19:3678-3681. [DOI: 10.11569/wcjd.v19.i36.3678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of LY294002 (a PI3K inhibitor) combined with gemcitabine on p-Akt and multidrug resistance-associated protein (MRP) expression in human pancreatic carcinoma PANC-1 cells.
METHODS: After PANC-1 cells were treated with different concentrations of LY294002 and gemcitabine, the expression of MRP mRNA and p-Akt and MRP proteins was detected by semi-quantitative RT-PCR and Western blot, respectively.
RESULTS: Compared to untreated control cells, treatment with LY294002 combined with gemcitabine significantly decreased the expression of MRP mRNA (1.47 ± 0.03, 1.31 ± 0.05, 1.02 ± 0.04, 0.76 ± 0.06, 0.37 ± 0.02, P < 0.05) and p-Akt and MRP proteins (p-Akt: 0.80±0.02, 0.63±0.01, 0.52±0.01, 0.41 ± 0.02, 0.35 ± 0.02, P < 0.05; MRP: 0.93 ± 0.05, 0.87 ± 0.03, 0.81 ± 0.03, 0.71 ± 0.02, 0.40 ± 0.03, both P < 0.05) in a concentration-dependent manner.
CONCLUSION: LY294002 could effectively strengthen the sensitivity of human pancreatic carcinoma PANC-1 cells to gemcitabine. LY294002 may down-regulate MRP transcription by inhibiting p-Akt expression and therefore reverse resistance of PANC-1 cells to gemcitabine.
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Seki T, Kokuryo T, Yokoyama Y, Suzuki H, Itatsu K, Nakagawa A, Mizutani T, Miyake T, Uno M, Yamauchi K, Nagino M. Antitumor effects of α-bisabolol against pancreatic cancer. Cancer Sci 2011; 102:2199-205. [PMID: 21883695 DOI: 10.1111/j.1349-7006.2011.02082.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
In the present study, we investigated whether α-bisabolol, a sesquiterpene alcohol present in essential oils derived from a variety of plants, has antitumor effects against pancreatic cancer. α-Bisabolol induced a decrease in cell proliferation and viability in pancreatic cancer cell lines (KLM1, KP4, Panc1, MIA Paca2), but not in pancreatic epithelial cells (ACBRI515). α-Bisabolol treatment induced apoptosis and suppressed Akt activation in pancreatic cancer cell lines. Furthermore, α-bisabolol treatment induced the overexpression of early growth response-1 (EGR1), whereas EGR1 siRNA decreased the α-bisabolol-induced cell death of KLM1 cells. Tumor growth in both subcutaneous and peritoneal xenograft nude mouse models was significantly inhibited by intragastric administration of 1000 mg/kg of α-bisabolol, once a week for three weeks. The results indicate that α-bisabolol could be a novel therapeutic option for the treatment of pancreatic cancer.
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Affiliation(s)
- Takashi Seki
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Shin-Kang S, Ramsauer VP, Lightner J, Chakraborty K, Stone W, Campbell S, Reddy SAG, Krishnan K. Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway. Free Radic Biol Med 2011; 51:1164-74. [PMID: 21723941 DOI: 10.1016/j.freeradbiomed.2011.06.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Revised: 05/18/2011] [Accepted: 06/05/2011] [Indexed: 12/21/2022]
Abstract
Tocotrienols are members of the vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG-CoA reductase pathway through posttranslational degradation and to suppress the activity of transcription factor NF-κB could be the basis for some of these properties. Our studies indicate that γ- and δ-tocotrienols have potent antiproliferative activity in pancreatic cancer cells (Panc-28, MIA PaCa-2, Panc-1, and BxPC-3). Indeed both tocotrienols induced cell death (>50%) by the MTT cell viability assay in all four pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the AKT and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and δ-tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6 kinase) in addition to suppressing the activation of protein kinase AKT. Suppression of activation of AKT by γ-tocotrienol led to downregulation of p-GSK-3β and upregulation accompanied by nuclear translocation of Foxo3. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3-kinase/AKT and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and need further investigation.
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Affiliation(s)
- Sonyo Shin-Kang
- Division of Hematology-Oncology, Department of Internal Medicine, JamesH. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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Kennedy AL, Adams PD, Morton JP. Ras, PI3K/Akt and senescence: Paradoxes provide clues for pancreatic cancer therapy. Small GTPases 2011; 2:264-267. [PMID: 22292129 DOI: 10.4161/sgtp.2.5.17367] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 07/25/2011] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is a leading cause of cancer-related death in the western world, and in most patients, current chemotherapies have negligible survival benefit. Evaluation of targeted therapies, however, is a relatively recent development. Paradoxically, mutations in KRAS, and in genes involved in one if its major effector pathways, the PI3K/Akt pathway, are often found simultaneously in human tumors. Accounting for this, we have recently found that activated PI3K/Akt signaling results in a weak senescence that actually impairs the stronger Ras-induced senescence. We showed that loss of Pten and thus activation of PI3K/Akt/mTOR signaling leads to acceleration of PDAC progression in mouse. Similarly, in humans, activation of PI3K/Akt/mTOR signaling correlated with poor patient survival. Importantly, these patients represent a discrete subpopulation of this disease in which PI3K/Akt/mTOR inhibitors might be effective. Reactivating senescence has recently emerged as a realistic outcome of cancer therapy. Clearly, promising treatments may work only in certain tumor subsets, or only as part of combinatorial approaches. Thus, careful consideration should be taken before selecting preclinical models and patient populations in which to test new agents.
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Zhou XK, Tang SS, Yi G, Hou M, Chen JH, Yang B, Liu JF, He ZM. RNAi knockdown of PIK3CA preferentially inhibits invasion of mutant PIK3CA cells. World J Gastroenterol 2011; 17:3700-8. [PMID: 21990951 PMCID: PMC3181455 DOI: 10.3748/wjg.v17.i32.3700] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2011] [Revised: 06/06/2011] [Accepted: 06/13/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effects of siRNA silencing of PIK3CA on proliferation, migration and invasion of gastric cancer cells and to investigate the underlying mechanisms.
METHODS: The mutation of PIK3CA in exons 9 and 20 of gastric cancer cell lines HGC-27, SGC-7901, BGC-823, MGC-803 and MKN-45 was screened by polymerase chain reaction (PCR) followed by sequencing. BGC-823 cells harboring no mutations in either of the exons, and HGC-27 cells containing PIK3CA mutations were employed in the current study. siRNA targeting PIK3CA was chemically synthesized and was transfected into these two cell lines in vitro. mRNA and protein expression of PIK3CA were detected by real-time PCR and Western blotting, respectively. We also measured phosphorylation of a serine/threonine protein kinase (Akt) using Western blotting. The proliferation, migration and invasion of these cells were examined separately by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing and Transwell chambers assay.
RESULTS: The siRNA directed against PIK3CA effectively led to inhibition of both endogenous mRNA and protein expression of PIK3CA, and thus significantly down-regulated phosphorylation of Akt (P < 0.05). Furthermore, simultaneous silencing of PIK3CA resulted in an obvious reduction in tumor cell proliferation activity, migration and invasion potential (P < 0.01). Intriguing, mutant HGC-27 cells exhibited stronger invasion ability than that shown by wild-type BGC-823 cells. Knockdown of PIK3CA in mutant HGC-27 cells contributed to a reduction in cell invasion to a greater extent than in non-mutant BGC-823 cells.
CONCLUSION: siRNA mediated targeting of PIK3CA may specifically knockdown the expression of PIK3CA in gastric cancer cells, providing a potential implication for therapy of gastric cancer.
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Abstract
Pancreatic cancer has a dismal prognosis and is the fourth most common cause of cancer related death in Western societies. In large part this is due to its typically late presentation, usually as locally advanced or metastatic disease. Identification of the non-invasive precursor lesions to pancreatic cancer raises the possibility of surgical treatment or chemoprevention at an early stage in the evolution of this disease, when more amenable to therapeutic interventions. Precursor lesions to pancreatic ductal adenocarcinoma, in particular pancreatic intraepithelial neoplasia (PanIN), have been recognised under a variety of synonyms for over 50 years. Over the past decade our understanding of the morphology, biological significance and molecular aberrations of these lesions has grown rapidly and there is now a widely accepted progression model integrating the accumulated morphological and molecular observations. Further progress is likely to be accelerated by improved mouse models of pancreatic cancer and by insight into the cancer genome gained by the International Cancer Genome Consortium (ICGC), in which an Australian consortium is leading the pancreatic cancer initiative. This review also outlines the morphological and molecular features of the other two precursors of pancreatic ductal adenocarcinoma, i.e., intraductal papillary mucinous neoplasms and mucinous cystic neoplasms.
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Sun C, Rosendahl AH, Andersson R, Wu D, Wang X. The role of phosphatidylinositol 3-kinase signaling pathways in pancreatic cancer. Pancreatology 2011; 11:252-260. [PMID: 21625196 DOI: 10.1159/000327715] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer is a highly malignant cancer and the fourth leading cause of cancer-related death. It is characterized by a rapid disease progression, a highly invasive tumor phenotype, and frequently resistance to chemotherapy. Despite significant advances in diagnosis, staging, and surgical management of the disease during the past decade, prognosis of pancreatic cancer is still dismal. METHODS AND RESULTS The phosphatidylinositol 3-kinase (PI3K) signaling pathways regulate cellular growth, metabolism, survival, and motility in pancreatic cancer. Pancreatic cancer is associated with a high degree of genetic alterations that can result in aberrant activation of the PI3K signaling pathway. Elucidating the role of the PI3K signaling pathway in pancreatic cancer may thus be both meaningful and necessary. CONCLUSION Improved knowledge of the PI3K signaling pathway in pancreatic cancer would furthermore be helpful in understanding mechanisms of tumor initiation and progression, and in identifying appropriate targeted anticancer treatment in pancreatic cancer. and IAP.
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Affiliation(s)
- Chen Sun
- Harbin Medical University, Harbin, China
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Hepatocyte growth factor inhibits anoikis of pancreatic carcinoma cells through phosphatidylinositol 3-kinase pathway. Pancreas 2011; 40:608-14. [PMID: 21499215 DOI: 10.1097/mpa.0b013e318214fa6c] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Escape from anoikis, apoptosis induced by loss of cell-cell or cell-extracellular matrix interactions, is important in tumor invasion and metastasis. Hepatocyte growth factor (HGF) is known to play a pivotal role in pancreatic carcinomas. This study aimed to determine the antianoikis effect of HGF in pancreatic carcinoma cells. METHODS Antianoikis effect of HGF was evaluated in human pancreatic carcinoma cells in nonadherent culture with or without anti-E-cadherin antibody. Signal pathways were investigated by Western blot analysis and inhibition assay using inhibitors for phosphatidylinositol 3-kinase and p38. RESULTS Pancreatic carcinoma cells underwent anoikis in nonadherent culture. However, some of the carcinoma cells survived by forming aggregations in suspension. Anti-E-cadherin antibody dissociated the aggregations, and the separated cells underwent additional anoikis. Hepatocyte growth factor inhibited anoikis irrespective of E-cadherin-mediated cell-cell contact. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway abolished the antianoikis effect of HGF. Phosphorylation of Akt was induced by HGF, and the phosphorylated Akt persisted even when E-cadherin was inhibited. CONCLUSIONS Hepatocyte growth factor inhibits anoikis of pancreatic carcinoma cells through phosphatidylinositol 3-kinase pathway in which activation of Akt may be involved. It is thus supposed that HGF may have a potent role in invasion and metastasis of pancreatic carcinoma cells by exerting its antianoikis effect.
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Kennedy AL, Morton JP, Manoharan I, Nelson DM, Jamieson NB, Pawlikowski JS, McBryan T, Doyle B, Oien KA, Enders GH, Zhang R, Sansom OJ, Adams PD. Activation of the PIK3CA/AKT pathway suppresses senescence induced by an activated RAS oncogene to promote tumorigenesis. Mol Cell 2011; 42:36-49. [PMID: 21474066 PMCID: PMC3145340 DOI: 10.1016/j.molcel.2011.02.020] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Revised: 09/24/2010] [Accepted: 01/27/2011] [Indexed: 01/27/2023]
Abstract
Mutations in both RAS and the PTEN/PIK3CA/AKT signaling module are found in the same human tumors. PIK3CA and AKT are downstream effectors of RAS, and the selective advantage conferred by mutation of two genes in the same pathway is unclear. Based on a comparative molecular analysis, we show that activated PIK3CA/AKT is a weaker inducer of senescence than is activated RAS. Moreover, concurrent activation of RAS and PIK3CA/AKT impairs RAS-induced senescence. In vivo, bypass of RAS-induced senescence by activated PIK3CA/AKT correlates with accelerated tumorigenesis. Thus, not all oncogenes are equally potent inducers of senescence, and, paradoxically, a weak inducer of senescence (PIK3CA/AKT) can be dominant over a strong inducer of senescence (RAS). For tumor growth, one selective advantage of concurrent mutation of RAS and PTEN/PIK3CA/AKT is suppression of RAS-induced senescence. Evidence is presented that this new understanding can be exploited in rational development and targeted application of prosenescence cancer therapies.
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Affiliation(s)
- Alyssa L. Kennedy
- Drexel University College of Medicine, Philadelphia, PA 19129, USA
- Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | | | | | - David M. Nelson
- CR-UK Beatson Labs, University of Glasgow, Glasgow, G61 1BD, UK
| | - Nigel B. Jamieson
- CR-UK Beatson Labs, University of Glasgow, Glasgow, G61 1BD, UK
- West of Scotland Pancreatic Unit, University Department of Surgery, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK
| | | | - Tony McBryan
- CR-UK Beatson Labs, University of Glasgow, Glasgow, G61 1BD, UK
| | - Brendan Doyle
- Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK
| | - Karin A. Oien
- CR-UK Beatson Labs, University of Glasgow, Glasgow, G61 1BD, UK
| | | | - Rugang Zhang
- Fox Chase Cancer Center, Philadelphia, PA, 19111, USA
| | - Owen J. Sansom
- Beatson Institute for Cancer Research, Glasgow, G61 1BD, UK
| | - Peter D. Adams
- CR-UK Beatson Labs, University of Glasgow, Glasgow, G61 1BD, UK
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Abstract
AIM: To determine the expression and activation of Akt in gastric cancer and to investigate the role of Akt activation in tumor angiogenesis in gastric cancer.
METHODS: Forty-eight fresh gastric adenocarcinoma tissue samples and matched normal gastric mucosal samples were collected surgically from patients with gastric cancer and immediately frozen in liquid nitrogen. The expression levels of Akt and phosphorylated Akt (pAkt) in the above tissue samples were measured by Western blot. Immunohistochemistry was conducted to evaluate the expression levels of pAkt and vascular endothelial growth factor (VEGF) and microvessel density (MVD) in gastric adenocarcinoma .
RESULTS: Western blot analysis demonstrated that Akt protein was expressed in 20 cancer tissue samples (20/20) and 19 normal tissue samples (19/20). The mean expression level of Akt protein in gastric adenocarcinoma was 2.7-fold higher than that in normal gastric mucosal tissue (0.186 ± 0.013 vs 0.069 ± 0.009, P < 0.001). The expression level of pAkt protein in gastric adenocarcinoma was 4.1-fold higher than that in tumor-adjacent gastric mucosal tissue (0.164 ± 0.025 vs 0.040 ± 0.006, P < 0.01). Immunohistochemically, pAkt was found to be expressed in 67.7% (32/48) of gastric cancer tissue samples and 58.3% (28/48) of normal tissue samples. The abundance of pAkt was significantly associated with tumor differentiation (χ2 = 8.280, P < 0.05) and TNM stage (χ2 = 8.526, P < 0.05). The mean MVD was 40.6 ± 15.1 in 48 gastric cancer tissue samples. The mean MVD in pAKT-positive cancer tissue samples was significantly higher than that in pAkt-negative ones (45.5 ± 20.3 vs 30.6 ± 12.1, P < 0.01). The mean MVD in VEGF-positive cancer tissue samples was significantly higher than that in VEGF-negative ones. In addition, pAkt abundance was significantly associated with VEGF expression (χ2 = 12.89, P = 0.012).
CONCLUSION: Overexpression of Akt and pAkt occurs in gastric adenocarcinoma and may promote tumor angiogenesis by up-regulating VEGF expression.
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Thosani N, Dasari CS, Bhutani MS, Raimondo M, Guha S. Molecular pathogenesis of intraductal papillary mucinous neoplasms of the pancreas. Pancreas 2010; 39:1129-1133. [PMID: 20881900 DOI: 10.1097/mpa.0b013e3181f66cdf] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Over the last 3 decades, there have been substantial improvements in diagnostic imaging and sampling techniques to evaluate pancreatic diseases. The modern technology has helped us to recognize premalignant conditions of pancreas including mucinous cystic neoplasms and intraductal papillary mucinous neoplasms (IPMNs). Differentiation between benign and malignant lesions and early detection of any malignant transformation in premalignant lesion are extremely important for further management decisions. Diagnostic cytology has limited sensitivity to further differentiate between benign, premalignant, and malignant lesions of the pancreas. There is limited information about the epidemiological risk factors and molecular mechanisms leading to development and further progression to malignancy of IPMNs. Several studies have shown that pancreatic juice and pancreatic tissue from the lesion can be tested for molecular markers including K-ras, p53, and p16 to differentiate between cancer and chronic inflammatory process. We review cellular signaling pathways that contribute to pathogenesis of IPMNs of the pancreas to further identify potential biomarkers and molecular targets.
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Affiliation(s)
- Nirav Thosani
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, TX, USA
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33
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Pdcd4 expression in intraductal papillary mucinous neoplasm of the pancreas: its association with tumor progression and proliferation. Hum Pathol 2010; 41:1507-15. [DOI: 10.1016/j.humpath.2010.02.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2009] [Revised: 02/25/2010] [Accepted: 02/26/2010] [Indexed: 01/11/2023]
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Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal 2010; 5:10. [PMID: 20642839 PMCID: PMC2915986 DOI: 10.1186/1750-2187-5-10] [Citation(s) in RCA: 307] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2010] [Accepted: 07/19/2010] [Indexed: 12/19/2022] Open
Abstract
Background Mammalian forkhead members of the class O (FOXO) transcription factors, including FOXO1, FOXO3a, and FOXO4, are implicated in the regulation of several biological processes, including the stress resistance, metabolism, cell cycle, apoptosis and DNA repair. The objectives of this study were to examine the molecular mechanisms by which FOXO transcription factors induced cell cycle arrest and apoptosis and enhanced anti-proliferative effects of sulforaphane (SFN, an active compound in cruciferous vegetables) in pancreatic cancer cells. Results Our data demonstrated that SFN inhibited cell proliferation and colony formation, and induced apoptosis through caspase-3 activation in pancreatic cancer cells. The inhibition of PI3K/AKT and MEK/ERK pathways activated FOXO transcription factors. SFN inhibited phosphorylation of AKT and ERK, and activated FOXO transcription factors, leading to cell cycle arrest and apoptosis. Phosphorylation deficient mutants of FOXO proteins enhanced FOXO transcriptional activity, and further enhanced SFN-induced FOXO activity and apoptosis. SFN induced the expression of p21/CIP1 and p27/KIP1, and inhibited the expression of cyclin D1. Conclusion These data suggest that inhibition of PI3K/AKT and ERK pathways acts together to activate FOXO transcription factor and enhances SFN-induced FOXO transcriptional activity, leading to cell cycle arrest and apoptosis.
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35
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Camaj P, Seeliger H, Ischenko I, Krebs S, Blum H, De Toni EN, Faktorova D, Jauch KW, Bruns CJ. EFEMP1 binds the EGF receptor and activates MAPK and Akt pathways in pancreatic carcinoma cells. Biol Chem 2010; 390:1293-302. [PMID: 19804359 DOI: 10.1515/bc.2009.140] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The EGF-related protein EFEMP1 (EGF-containing fibulin-like extracellular matrix protein 1) has been shown to promote tumor growth in human adenocarcinoma. To understand the mechanism of this action, the signal transduction activated upon treatment with this protein has been investigated. We show that EFEMP1 binds EGF receptor (EGFR) in a competitive manner relative to epidermal growth factor (EGF), implicating that EFEMP1 and EGF share the same or adjacent binding sites on the EGFR. Treatment of pancreatic carcinoma cells with purified EFEMP1 activates autophosphorylation of EGFR at the positions Tyr-992 and Tyr-1068, but not at the position Tyr-1048. This signal is further transduced to phosphorylation of Akt at position Thr-308 and p44/p42 MAPK (mitogen-activated protein kinase) at positions Thr-202 and Tyr-204. These downstream phosphorylation events can be inhibited by treatment with the EGFR kinase inhibitor PD 153035. The observed signal transduction upon treatment with EFEMP1 can contribute to the enhancement of tumor growth shown in pancreatic carcinoma cells overexpressing EFEMP1.
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Affiliation(s)
- Peter Camaj
- Department of Surgery, Munich University Medical Center, Campus Grosshadern, Marchioninistr. 15, D-81377 Munich, Germany
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36
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Buchholz M, Gress TM. Molecular changes in pancreatic cancer. Expert Rev Anticancer Ther 2009; 9:1487-97. [PMID: 19828010 DOI: 10.1586/era.09.107] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
As with many human malignancies, pancreatic cancer is a complex genetic disorder. Several thousand disease-associated alterations on the DNA, mRNA, miRNA and protein levels have been reported to date. Some of these alterations, including a number of gatekeeper mutations, which are of pre-eminent importance for the onset and progression of the disease, have been extensively studied in primary tissues, in vitro experiments and transgenic mouse models. For the vast majority of alterations, however, data about the functional significance are lacking. The situation is complicated by the fact that no certainty exists concerning the identity of the cells that originally undergo malignant transformation nor about the precise nature and fate of premalignant lesions that are observed in pancreatic tissues.
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Affiliation(s)
- Malte Buchholz
- Klinik f. Innere Medizin, SP Gastroenterologie, Universitätsklinikum Marburg, Baldingerstrasse 35043 Marburg, Germany.
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37
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Synergistic action of Smad4 and Pten in suppressing pancreatic ductal adenocarcinoma formation in mice. Oncogene 2009; 29:674-86. [PMID: 19901970 DOI: 10.1038/onc.2009.375] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Mutations of SMAD4/DPC4 are found in about 60% of human invasive pancreatic ductal adenocarcinomas (PDACs); yet, the manner in which SMAD4 deficiency enhances tumorigenesis remains elusive. Using a Cre-LoxP approach, we generated a mutant mouse carrying a targeted deletion of Smad4 in the pancreas. We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy. To investigate this, we disrupted both Pten and Smad4. We showed that Pten deficiency initiated widespread premalignant lesions, and a low tumor incidence that was significantly accelerated by Smad4-deficiency. The absence of Smad4 in a Pten-mutant background enhanced cell proliferation and triggered transdifferentiation from acinar, centroacinar and islet cells, accompanied by activation of Notch1 signaling. We showed that all tumors developed in the Smad4/Pten-mutant pancreas exhibited high levels of pAKT and mTOR, and that about 50 and 83% of human pancreatic cancers examined showed increased pAKT and pmTOR, respectively. Besides the similarity in gene expression, the pAKT and/or pmTOR-positive human PDACs and mouse pancreatic tumors also shared some histopathological similarities. These observations indicate that Smad4/Pten-mutant mice mimic the tumor progression of human pancreatic cancers that are driven by activation of the AKT-mTOR pathway, and uncovered a synergistic action of Smad4 and Pten in repressing pancreatic tumorigenesis.
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38
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Genetic alterations in precancerous pancreatic lesions and their clinical implications. ACTA ACUST UNITED AC 2009; 33:1028-35, e1-9. [DOI: 10.1016/j.gcb.2009.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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39
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Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas. Br J Cancer 2009; 100:1438-43. [PMID: 19352382 PMCID: PMC2694421 DOI: 10.1038/sj.bjc.6604986] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
We have previously shown that WW domain-containing oxidoreductase (WWOX) has tumour-suppressing effects and that its expression is frequently reduced in pancreatic carcinoma. In this study, we examined WWOX expression in intraductal papillary mucinous neoplasm of the pancreas (IPMN) to assess the function of WWOX in pancreatic duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chain reaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas (IPMAs) and intraductal papillary mucinous carcinomas (IPMCs), loss or reduced WWOX immunoreactivity was detected in 3 (15%) of 20 IPMAs and 17 (81%) of 21 IPMCs. In addition, hypermethylation of the WWOX regulatory site was detected in 1 (33%) of 3 WWOX(−) IPMAs and 9 (53%) of 17 WWOX(−) IPMCs, suggesting that hypermethylation may possibly be important in the suppression of WWOX expression. Reduction of WWOX expression was significantly correlated with a higher Ki-67 labelling index but was not correlated with the ssDNA apoptotic body index. Interestingly, decreased WWOX expression was significantly correlated with loss of SMAD4 expression in these IPMNs. The results indicate that downregulation of WWOX expression by the WWOX regulatory region hypermethylation is critical for transformation of pancreatic duct.
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40
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Antonello D, Gobbo S, Corbo V, Sipos B, Lemoine NR, Scarpa A. Update on the molecular pathogenesis of pancreatic tumors other than common ductal adenocarcinoma. Pancreatology 2008; 9:25-33. [PMID: 19077452 DOI: 10.1159/000178872] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Although ductal adenocarcinoma is the most common and well known pancreatic tumor type, other distinct epithelial neoplasms affecting the pancreas that show different symptoms, biological behaviors and outcomes are becoming more frequently recognized and documented. Pancreatic epithelial tumors may be separated into ductal and nonductal neoplasms. The former group includes pancreatic ductal adenocarcinoma, intraductal papillary-mucinous tumor, mucinous cystic tumor and serous cystic tumor. The latter group includes pancreatic endocrine tumor, pancreatic acinar cell carcinoma, pancreatoblastoma and solid-pseudopapillary tumor. The aim of this review is to summarize recently acquired knowledge regarding the molecular characterization of these uncommon pancreatic epithelial neoplasms. RECENT FINDINGS Molecular studies of uncommon pancreatic epithelial tumors suggest that the different morphological entities are associated with distinct molecular profiles, highlighting the involvement of different molecular pathways leading to the development of each subtype of pancreatic neoplasm. CONCLUSION The correct classification of rare pancreatic epithelial tumors and the identification of their characteristic molecular aspects is the fundamental starting point in identifying novel diagnostic molecular tools and new targets for innovative therapeutic strategies.
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Affiliation(s)
- D Antonello
- Dipartimento di Patologia, Università di Verona, Verona, Italy
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41
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Abstract
Pancreatic cancer is a lethal disease and notoriously difficult to treat. Only a small proportion is curative by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Clearly there is a need for the continual development of novel therapeutic agents to improve the current situation. Improvement of our understanding of the disease has generated a large number of studies on biological approaches targeting the molecular abnormalities of pancreatic cancer, including gene therapy and signal transduction inhibition, antiangiogenic and matrix metalloproteinase inhibition, oncolytic viral therapy and immunotherapy. This article provides a review of these approaches, both investigated in the laboratories and in subsequent clinical trials.
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Affiliation(s)
- Han Hsi Wong
- Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK.
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42
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Pham NA, Schwock J, Iakovlev V, Pond G, Hedley DW, Tsao MS. Immunohistochemical analysis of changes in signaling pathway activation downstream of growth factor receptors in pancreatic duct cell carcinogenesis. BMC Cancer 2008; 8:43. [PMID: 18254976 PMCID: PMC2270852 DOI: 10.1186/1471-2407-8-43] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2007] [Accepted: 02/06/2008] [Indexed: 01/12/2023] Open
Abstract
Background The pathogenesis of pancreatic ductal adenocarcinoma (PDAC) involves multi-stage development of molecular aberrations affecting signaling pathways that regulate cancer growth and progression. This study was performed to gain a better understanding of the abnormal signaling that occurs in PDAC compared with normal duct epithelia. Methods We performed immunohistochemistry on a tissue microarray of 26 PDAC, 13 normal appearing adjacent pancreatic ductal epithelia, and 12 normal non-PDAC ducts. We compared the levels of 18 signaling proteins including growth factor receptors, tumor suppressors and 13 of their putative downstream phosphorylated (p-) signal transducers in PDAC to those in normal ductal epithelia. Results The overall profiles of signaling protein expression levels, activation states and sub-cellular distribution in PDAC cells were distinguishable from non-neoplastic ductal epithelia. The ERK pathway activation was correlated with high levels of S2448p-mTOR (100%, p = 0.05), T389p-S6K (100%, p = 0.02 and S235/236p-S6 (86%, p = 0.005). Additionally, T389p-S6K correlated with S727p-STAT3 (86%, p = 0.005). Advanced tumors with lymph node metastasis were characterized by high levels of S276p-NFκB (100%, p = 0.05) and S9p-GSK3β (100%, p = 0.05). High levels of PKBβ/AKT2, EGFR, as well as nuclear T202/Y204p-ERK and T180/Y182p-p38 were observed in normal ducts adjacent to PDAC compared with non-cancerous pancreas. Conclusion Multiple signaling proteins are activated in pancreatic duct cell carcinogenesis including those associated with the ERK, PKB/AKT, mTOR and STAT3 pathways. The ERK pathway activation appears also increased in duct epithelia adjacent to carcinoma, suggesting tumor micro-environmental effects.
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Affiliation(s)
- Nhu-An Pham
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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43
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Yip-Schneider MT, Wu H, Ralstin M, Yiannoutsos C, Crooks PA, Neelakantan S, Noble S, Nakshatri H, Sweeney CJ, Schmidt CM. Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibition in vivo. Mol Cancer Ther 2007; 6:1736-1744. [PMID: 17541034 DOI: 10.1158/1535-7163.mct-06-0794] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-kappaB (NF-kappaB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-kappaB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/COX-2 levels or activity in any of the treatment groups. NF-kappaB DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents.
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Furukawa T. Molecular genetics of intraductal papillary-mucinous neoplasms of the pancreas. ACTA ACUST UNITED AC 2007; 14:233-7. [PMID: 17520197 DOI: 10.1007/s00534-006-1167-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2006] [Accepted: 04/11/2006] [Indexed: 12/23/2022]
Abstract
Intraductal papillary-mucinous neoplasms of the pancreas show characteristic clinicopathological and molecular pathobiological features which are distinct from those of conventional ductal adenocarcinomas. Alterations of KRAS, AKT/PKB, CDKN2A, TP53, SMAD4, STK11/LKB1, and DUSP6, and other molecular alterations, including global expression studies as well as their clinical implications, are discussed.
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MESH Headings
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/metabolism
- Adenocarcinoma, Mucinous/pathology
- Adenocarcinoma, Papillary/genetics
- Adenocarcinoma, Papillary/metabolism
- Adenocarcinoma, Papillary/pathology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- DNA, Neoplasm/genetics
- Disease Progression
- Dual Specificity Phosphatase 6/genetics
- Dual Specificity Phosphatase 6/metabolism
- Gene Expression Regulation, Neoplastic
- Humans
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Prognosis
- Smad4 Protein/genetics
- Smad4 Protein/metabolism
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Affiliation(s)
- Toru Furukawa
- International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo 162-8666, Japan
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Liau SS, Jazag A, Whang EE. RETRACTED: HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma. Cancer Res 2006; 66:11613-22. [PMID: 17178855 DOI: 10.1158/0008-5472.can-06-1460] [Citation(s) in RCA: 93] [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
HMGA1 proteins are architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. We hypothesized that HMGA1 expression is a determinant of cellular invasiveness and metastasis in pancreatic cancer. Stable silencing of HMGA1 in MiaPaCa2 and PANC1 pancreatic adenocarcinoma cells was achieved by transfection of short hairpin RNA-generating vectors. Additionally, stable overexpression of HMGA1 in MiaPaCa2 cells (characterized by low levels of inherent HMGA1 expression) was achieved. HMGA1 silencing resulted in significant reductions in cellular invasiveness through Matrigel; in cellular matrix metalloproteinase-9 (MMP-9) activity, mRNA levels, and gene promoter activity; and in Akt phosphorylation at Ser(473). Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels, and promoter activity; and in Akt phosphorylation at Ser(473). HMGA1 overexpression-induced increases in invasiveness were MMP-9 dependent. The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs. Akt-dependent modulation of MMP-9 activity contributed significantly to HMGA1 overexpression-induced increases in invasive capacity. Furthermore, HMGA1 silencing resulted in reductions in metastatic potential and tumor growth in vivo and in tumoral MMP-9 activity. Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma.
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Affiliation(s)
- Siong-Seng Liau
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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Doucas H, Garcea G, Neal CP, Manson MM, Berry DP. Chemoprevention of pancreatic cancer: a review of the molecular pathways involved, and evidence for the potential for chemoprevention. Pancreatology 2006; 6:429-39. [PMID: 16847380 DOI: 10.1159/000094560] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer has a poor prognosis. The use of drugs or natural agents which inhibit or slow down tumour growth therefore has important potential in the development of future therapies. METHODS A literature search of the PubMed and ISI Web of Science databases was undertaken to review the current data available on the alterations in signalling pathways found in pancreatic carcinogenesis, in order to identify sites that could be targeted by chemopreventive agents. Several agents of particular relevance to pancreatic cancer were identified, and their possible mechanisms of action reviewed. RESULTS Chemopreventive agents such as non-steroidal anti-inflammatory drugs, green tea constituents, and antioxidants have been shown to target various steps in intracellular signalling pathways, particularly those controlling cell proliferation and survival. Work on cell lines and animal models has shown that some of these agents may be able to modulate the growth of pancreatic tumours. Initial clinical trials of some chemopreventives in pancreatic cancer have been undertaken, and have yielded mixed results, prompting the need for further studies. CONCLUSION As the molecular pathology of pancreatic cancer becomes better understood, sites of action of chemopreventive substances have been uncovered. Several agents have shown promising results by their ability to inhibit pancreatic carcinogenesis in laboratory studies. If these effects can be successfully translated into human studies then these agents may prove to be valuable adjuvant therapies in the future.
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Affiliation(s)
- H Doucas
- Department of Cancer Studies and Molecular Medicine, Biocentre, Leicester, UK.
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47
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Brunner TB, Cengel KA, Hahn SM, Wu J, Fraker DL, McKenna WG, Bernhard EJ. Pancreatic cancer cell radiation survival and prenyltransferase inhibition: the role of K-Ras. Cancer Res 2005; 65:8433-41. [PMID: 16166322 DOI: 10.1158/0008-5472.can-05-0158] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Activating K-ras mutations are found in approximately 90% of pancreatic carcinomas and may contribute to the poor prognosis of these tumors. Because radiotherapy is frequently used in pancreatic cancer treatment, we assessed the contribution of oncogenic K-ras signaling to pancreatic cancer radiosensitivity. Seven human pancreatic carcinoma lines with activated K-ras and two cell lines with wild-type ras were used to examine clonogenic cell survival after Ras inhibition. Ras inhibition was accomplished by small interfering RNA (siRNA) knockdown of K-ras expression and by blocking Ras processing using a panel of prenyltransferase inhibitors of differing specificity for the two prenyltransferases that modify K-Ras. K-ras knockdown by siRNA or inhibition of prenyltransferase activity resulted in radiation sensitization in vitro and in vivo in tumors with oncogenic K-ras mutations. Inhibition of farnesyltransferase alone was sufficient to radiosensitize most K-ras mutant tumors, although K-Ras prenylation was not blocked. These results show that inhibition of activated K-Ras can promote radiation killing of pancreatic carcinoma in a superadditive manner. The finding that farnesyltransferase inhibition alone radiosensitizes tumors with K-ras mutations implies that a farnesyltransferase inhibitor-sensitive protein other than K-Ras may contribute to survival in the context of mutant K-ras. Farnesyltransferase inhibitors could therefore be of use as sensitizers for pancreatic carcinoma radiotherapy.
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Affiliation(s)
- Thomas B Brunner
- Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6072, USA
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Moriya T, Kimura W, Semba S, Sakurai F, Hirai I, Ma J, Fuse A, Maeda K, Yamakawa M. Biological similarities and differences between pancreatic intraepithelial neoplasias and intraductal papillary mucinous neoplasms. ACTA ACUST UNITED AC 2005; 35:111-9. [PMID: 15879625 DOI: 10.1385/ijgc:35:2:111] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Ever since the classification of pancreatic intraepithelial neoplasia (PanIN) was published, studies on the precursor lesions of pancreatic cancer have been advancing along a new directions, using standardized terminology. There are few studies that have examined the biological differences between PanIN and intraductal papillary mucinous neoplasm (IPMN) in detail. AIMS PanIN and IPMN, which are similar in morphology, were compared using various indicators, with the aim of identifying the similarities and differences between the two. METHODOLOGY A total of 46 PanINs and 37 ducts with IPMN were identified in 19 patients with invasive ductal carcinoma and 18 patients with IPMN. These PanINs and IPMNs were examined immunohistologically with respect to the expression patterns of HER2/neu, DPC4/Smad4, Akt/PKB, p53, cyclin A, Ki67, MUC1, and MUC2. RESULTS Significant differences in the expression of MUC1 and MUC2 were observed between IPMNadenoma and PanIN-2 and between CIS and PanIN-3 (MUC1: p = 0.001 and p = 0.005, respectively; MUC2: p = 0.002 and p < 0.001, respectively). A significant difference in the p53 expression level was also observed between CIS and PanIN-3 (p = 0.015). CONCLUSIONS In both IPMN and PanIN, the grade of atypism increased with increasing expression of HER2/neu, DPC4/Smad4, and Akt/PKB, along with progression in the process of multistage carcinogenesis. Although the expression levels of these factors reflected the grade of atypism, they did not reflect any differences in the grade of biological malignancy between IPMN and PanIN. On the other hand, MUC1 and MUC2 may serve as indicators of the direction of differentiation, i.e., either progression to IDAC or IPMN. Positivity for MUC1 was believed to suggest differentiation into IDAC, and positivity for MUC2 appeared to be indicative of differentiation into IPMN. Such indication of the direction of differentiation seemed to appear in PanIN1-2, even before abnormalities of HER2/neu, Akt/PKB, DPC4/Smad4, p53, and cyclin A expression began to be detected.
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Affiliation(s)
- Toshiyuki Moriya
- First Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan
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Bellacosa A, Kumar CC, Di Cristofano A, Testa JR. Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 2005; 94:29-86. [PMID: 16095999 DOI: 10.1016/s0065-230x(05)94002-5] [Citation(s) in RCA: 629] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. An ever-increasing list of AKT substrates has precisely defined the multiple functions of this kinase family in normal physiology and disease states. Cellular processes regulated by AKT include cell proliferation and survival, cell size and response to nutrient availability, intermediary metabolism, angiogenesis, and tissue invasion. All these processes represent hallmarks of cancer, and a burgeoning literature has defined the importance of AKT alterations in human cancer and experimental models of tumorigenesis, continuing the legacy represented by the original identification of v-Akt as the transforming oncogene of a murine retrovirus. Many oncoproteins and tumor suppressors intersect in the AKT pathway, finely regulating cellular functions at the interface of signal transduction and classical metabolic regulation. This careful balance is altered in human cancer by a variety of activating and inactivating mechanisms that target both AKT and interrelated proteins. Reprogramming of this altered circuitry by pharmacologic modulation of the AKT pathway represents a powerful strategy for rational cancer therapy. In this review, we summarize a large body of data, from many types of cancer, indicating that AKT activation is one of the most common molecular alterations in human malignancy. We also review mechanisms of activation of AKT kinases, examples of therapeutic modulation of the AKT pathway in animal models, and the current status of efforts to target molecular components of the AKT pathway for cancer therapy and, possibly, cancer prevention.
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Affiliation(s)
- Alfonso Bellacosa
- Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
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Watanabe H, Saito H, Rychahou PG, Uchida T, Evers BM. Aging is associated with decreased pancreatic acinar cell regeneration and phosphatidylinositol 3-kinase/Akt activation. Gastroenterology 2005; 128:1391-404. [PMID: 15887120 DOI: 10.1053/j.gastro.2005.03.016] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The effects of aging on pancreatic acinar cell proliferation have not been clearly defined. Phosphatidylinositol 3-kinase (PI3K)-mediated phosphorylation of Akt is a critical step for proliferation of various cell types and insulin secretion from pancreatic endocrine cells; however, its role in acinar cell proliferation is not known. The purpose of this study was to (1) delineate the effects of aging on pancreatic regeneration after partial pancreatectomy (Px) and (2) define the involvement of the PI3K/Akt pathway in pancreatic regeneration. METHODS Following partial Px, pancreatic regeneration and activation of the PI3K pathway were compared in young and aged mice. Activation of the PI3K/Akt pathway was evaluated by Akt phosphorylation (pAkt). The role of the PI3K pathway in pancreatic regeneration after partial Px was assessed by effects of a pharmacologic PI3K inhibitor wortmannin or small interfering RNA (siRNA) to the p85alpha regulatory subunit. To confirm further the critical role of the PI3K/Akt pathway in pancreatic acinar cell proliferation, IGF-1-mediated cell proliferation was determined in cultured acinar cells pretreated with wortmannin or p85alpha siRNA. RESULTS Pancreatic regeneration and pAkt expression after partial Px were significantly decreased with aging. Treatment with wortmannin or p85alpha siRNA reduced pancreatic regeneration after partial Px. The IGF-1-mediated cell proliferation in vitro was completely blocked by wortmannin or p85alpha siRNA but not by the MEK/ERK inhibitor PD98059. CONCLUSIONS PI3K/Akt activation plays a critical role in the regeneration of pancreatic acini after resection. Furthermore, pancreatic regeneration is markedly attenuated in the aged pancreas most likely because of decreased PI3K/Akt activation.
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Affiliation(s)
- Hiroaki Watanabe
- Department of Surgery, The University of Texas Medical Branch, Galveston 77555-0536, USA
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