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Miao H, Zhang B, Li Y, Ma X, Yang Y, Lin Z, Liu Y. Rosuvastatin inhibits carcinogenesis through Ca 2+ triggered endoplasmic reticulum stress pathway in pancreatic cancer. Cell Signal 2025; 131:111753. [PMID: 40107481 DOI: 10.1016/j.cellsig.2025.111753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Revised: 02/17/2025] [Accepted: 03/16/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND Pancreatic cancer remains one of the most challenging malignancies to treat due to its late-stage diagnosis, aggressive progression, and high resistance to existing therapies. Rosuvastatin (ROV), known for its hypolipidemic effects, which significantly inhibited clonogenic capacity and epithelial-mesenchymal transition (EMT) in prostate cancer cells. However, the anti-cancer mechanisms of ROV in PC have not yet been fully explored. PURPOSE This study aimed to investigate the potential anti-cancer effects of ROV on PC cells and to elucidate the underlying mechanisms. METHODS Cytotoxicity was detected via MTT assay, while epithelial-mesenchymal transition (EMT) markers, Ca2+ levels, and endoplasmic reticulum (ER) stress were observed with fluorescence microscopy. RNA-seq analysis was used to identify significantly changed mRNA expression following ROV treatment. Additionally, western blotting and immunohistochemistry (IHC) were conducted to examine proteins involving in the cell cycle, EMT, Ca2+ signaling, and endoplasmic reticulum stress (ERS) in vitro and in vivo. RESULTS ROV inhibited PC cell proliferation by arresting the cell cycle at the G1/S phase and partially reducing cell mobility during the EMT process. A total of 1336 significantly different RNAs (P < 0.05 and |logFC|>1) were identified and analyzed through RNA-seq, revealing the Ca2+ and ER pathways in PC cells treated with ROV. ROV treatment significantly altered the level of intracellular Ca2+, triggering the ERS pathway and modulating the Ca2+/CaM/CaMKII/ERK pathway. Furthermore, ROV inhibited key proteins within the Ca2+ and ERS pathways, leading to reduced cell proliferation, mobility and G1/S phase arrest. In tumor tissues, the expression of Ki67, EMT markers, Calmodulin, and ATF6 corroborated the in vitro findings. CONCLUSION ROV inhibited proliferation and metastasis in PC cells by inhibiting the EMT process through the Ca2+/CaM/CaMKII/ERK and Ca2+-mediated ERS pathways, highlighting its potential as a prophylactic and therapeutic agent for PC.
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Affiliation(s)
- Hui Miao
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Dunhua City Hospital, Dunhua 133700, China
| | - Baojian Zhang
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Yue Li
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Xiao Ma
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Yang Yang
- Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Zhenhua Lin
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China
| | - Yanqun Liu
- Central Laboratory, Yanbian University Hospital, Yanji 133000, China; Key Laboratory of Pathobiology (Yanbian University), State Ethnic Affairs Commission, Yanji 133002, China.
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Paul JK, Azmal M, Talukder OF, Ghosh A. Statin use and Pancreatic Cancer: A Meta-analysis of its Association with Incidence in the General Population and Survival in Patients. J Gastrointest Cancer 2025; 56:121. [PMID: 40379858 DOI: 10.1007/s12029-025-01238-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2025] [Indexed: 05/19/2025]
Abstract
PURPOSE Statins have been appearing as a potential anti-cancer agent in numerous studies. The study aimed to unravel the impact of statins in pancreatic cancer in terms of reducing the occurrence (morbidity) and improving survival (mortality). METHODS A comprehensive search of databases was carried out to collect the eligible studies up to July 2024. This meta-analysis evaluates two distinct questions: (1) whether statin use reduces the incidence of pancreatic ductal adenocarcinoma (PDAC) in the general population, and (2) whether statins improve survival among patients diagnosed with PDAC. In total, 39 studies were included in the meta-analysis, comprising 15 case-control studies, 20 cohort studies, three randomized controlled trials, and one non-randomized controlled trial. A generic inverse variance weighted random-effects model was applied to calculate the pooled risk ratio and 95% confidence intervals. Subgroup analyses were performed based on the availability of relevant information. RESULTS In the total meta-analysis, aggregated results demonstrated a substantial decrease in pancreatic cancer risk in all statin users (RR 0.94; 95% CIs, 0.90-0.97, and p-value = 0.0008). The pooled risk ratio estimate of lipophilic statins was 0.97 (95% CI, 0.87-1.07; P = 0.50; I2 = 0.0%). The estimated pooled risk ratios of long-term and short-term statin use were 0.80 (95% CI, 0.69-0.92; P = 0.002; I2 = 42%) and 0.86 (95% CI, 0.70-1.06; P = 0.15; I2 = 96%), respectively. For long-term and short-term follow-up, the risk ratios were 0.81 (95% CI, 0.70-0.94; P = 0.007; I2 = 55%) and 0.96 (95% CI, 0.90-1.02; P = 0.16; I2 = 26%), respectively. As for the studies collectively, heterogeneity was tested using the Cochrane chi square test (p-value = = 0.40, I2 = 4%). No publication bias was found. CONCLUSION The overall outcome of the study indicates that statins might lower the occurrence and increase the survival of PDAC patients.
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Affiliation(s)
- Jibon Kumar Paul
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh
| | - Mahir Azmal
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh
| | - Omar Faruk Talukder
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh
| | - Ajit Ghosh
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, 3114, Bangladesh.
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Saito K, Nakai Y, Sasaki T, Takeda T, Ueno M, Tezuka S, Isayama H, Tomishima K, Kojima Y, Yamamoto N, Ito Y, Oyama H, Toda N, Takagi K, Matsubara S, Mohri D, Sato T, Fujishiro M. Impact of Statin Use on Survival in Patients With Unresectable Pancreatic cancer Receiving Gemcitabine Plus Nab-Paclitaxel: A Multicenter Retrospective Study. Pancreas 2025; 54:e107-e113. [PMID: 39928888 DOI: 10.1097/mpa.0000000000002411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2025]
Abstract
PURPOSE The aim of this multicenter retrospective study was to evaluate the impact of statin use on clinical outcomes in patients with unresectable pancreatic cancer (PC) receiving gemcitabine plus nab-paclitaxel (GnP) in a large Japanese cohort. MATERIALS AND METHODS We retrospectively reviewed the medical records including data on the use of concomitant medications in patients with unresectable PC receiving GnP between January 2015 and January 2019 at 10 hospitals. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS A total of 1682 patients were included in the analysis; of which 322 patients (19%) received statins and 1360 (81%) did not receive statin. The median PFS and OS were 7.5 versus 7.3 months (P = 0.87) and 15.1 versus 14.4 months (P = 0.48) in cases with and without statin use. The use of statin was not associated with PFS (hazard ratio, 1.01; 95% confidence interval, 0.85-1.18, P = 0.93) or OS (hazard ratio, 1.05; 95% confidence interval, 0.91-1.21, P = 0.47) in the multivariable analyses. PFS and OS did not significantly differ by liposolubility of statins, either. CONCLUSIONS Stain use was not associated with PFS or OS in patients with unresectable PC receiving GnP.
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Affiliation(s)
| | | | - Takashi Sasaki
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tsuyoshi Takeda
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shun Tezuka
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Ko Tomishima
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yasushi Kojima
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Natsuyo Yamamoto
- Department of Gastroenterology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yukiko Ito
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | | | - Nobuo Toda
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Kaoru Takagi
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Saburo Matsubara
- Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Dai Mohri
- Department of Gastroenterology, JR Tokyo general hospital, Tokyo, Japan
| | | | - Mitsuhiro Fujishiro
- From the Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Su B, Fan Z, Wu J, Zhan H. Genetic association of lipid-lowering drug target genes with pancreatic cancer: a Mendelian randomization study. Sci Rep 2025; 15:3282. [PMID: 39863728 PMCID: PMC11762976 DOI: 10.1038/s41598-025-87490-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025] Open
Abstract
Previous studies have found that dyslipidemia is a risk factor for pancreatic cancer (PC), and that lipid-lowering drugs may reduce the risk of PC. However, it is not clear whether dyslipidemia causes PC. The Mendelian randomization (MR) study aimed to investigate the causal role of lipid traits in pancreatic cancer and to assess the potential impact of lipid-lowering drug targets on pancreatic cancer. Genetic variants associated with lipid traits and variants of genes encoding lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Summary statistics for PC were obtained from an independent GWAS datasets. Colocalization analyses were performed to validate the robustness of the results. No significant effect of lipid-lowering drug targets on PC risk was found. Genetic mimicry of lipoprotein lipase (LPL) was potentially associated with PC risks. Significant MR associations were observed in the discovery dataset (OR 1.64 [95% CI 1.24-2.16], p = 4.48*10-4) with PC in one dataset. However, the finding was not verified in the replication dataset. Our findings do not support dyslipidemia as a causal factor for PC. Among lipid-lowering drug targets, LPL is the potential drug target in PC.
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Affiliation(s)
- Bohan Su
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Zhiyao Fan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Jiexi Wu
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Hanxiang Zhan
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China.
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Zhan Y, Zhang K, Fan Y, Lin S, Wu J, Xu H. Lipids, lipid-lowering drug target genes and pancreatic cancer: a Mendelian randomization study. Int J Clin Pharm 2025:10.1007/s11096-025-01866-7. [PMID: 39821006 DOI: 10.1007/s11096-025-01866-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/04/2025] [Indexed: 01/19/2025]
Abstract
BACKGROUND Pancreatic cancer (PC) is a malignant tumor with a low survival rate. Lipid modifiers show potential for PC therapy, but evidence is lacking. AIM This Mendelian randomization (MR) study aimed to explore the relationship between lipid traits, and lipid-lowering drug target genes with PC risk. METHOD Genetic instrumental variables associated with lipid traits and lipid-lowering drug target genes were used to perform MR analyses of PC risk. MR estimation was based on genome-wide association study data from two large sample sets, and the MR results were meta-analyzed to assess their impact on PC risk. To ensure the reliability of lipid-modifying drug targets, we conducted a Summary Data-based Mendelian Randomization (SMR) analysis. Additionally, a two-step MR analysis was employed to explore potential mediating effects. RESULTS In two independent datasets, HMG-CoA reductase (HMGCR) inhibition was statistically associated with a lower risk of PC (OR 0.50, [95% CI 0.25-1.00]; p = 0.0453). The results were further supported by SMR analysis, which showed a similar association (OR 0.51, [95% CI 0.28-0.96]; p = 0.0369). Mediation analysis revealed that 11.69% of the protective effect of HMGCR inhibitors on PC is mediated through lower BMI levels. No significant effect of lipid traits and the other eight lipid-lowering drug targets on PC risk was found. CONCLUSION This study suggests that HMGCR may be a potential drug target for the treatment or prevention of PC, providing important insights into the use of lipid-targeted drugs in PC therapy.
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Affiliation(s)
- Yuxuan Zhan
- School of Public Health and Institute of Wenzhou and Liangzhu Laboratory, Zhejiang University, Hangzhou, 310058, China
| | - Kai Zhang
- School of Public Health and Institute of Wenzhou and Liangzhu Laboratory, Zhejiang University, Hangzhou, 310058, China
| | - Yiqun Fan
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Siyi Lin
- School of Public Health and Institute of Wenzhou and Liangzhu Laboratory, Zhejiang University, Hangzhou, 310058, China
| | - Jian Wu
- School of Public Health and Institute of Wenzhou and Liangzhu Laboratory, Zhejiang University, Hangzhou, 310058, China
| | - Hongxia Xu
- School of Public Health and Institute of Wenzhou and Liangzhu Laboratory, Zhejiang University, Hangzhou, 310058, China.
- Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
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6
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Kubota CS, Myers SL, Seppälä TT, Burkhart RA, Espenshade PJ. In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency. Mol Metab 2024; 85:101964. [PMID: 38823776 PMCID: PMC11217740 DOI: 10.1016/j.molmet.2024.101964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 05/04/2024] [Accepted: 05/28/2024] [Indexed: 06/03/2024] Open
Abstract
OBJECTIVE Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. In this study, we examined the requirement of SREBP target genes for pancreatic ductal adenocarcinoma (PDAC) tumor growth. METHODS Here we constructed a custom CRISPR knockout library containing known SREBP target genes and performed in vitro 2D culture and in vivo orthotopic xenograft CRISPR screens using a patient-derived PDAC cell line. In vitro, we grew cells in medium supplemented with 10% fetal bovine serum (FBS) or 10% lipoprotein-deficient serum (LPDS) to examine differences in gene essentiality in different lipid environments. In vivo, we injected cells into the pancreata of nude mice and collected tumors after 4 weeks. RESULTS We identified terpenoid backbone biosynthesis genes as essential for PDAC tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that geranylgeranyl diphosphate synthase 1 (GGPS1) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model. CONCLUSIONS These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
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Affiliation(s)
- Casie S Kubota
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Stephanie L Myers
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Molecular & Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Toni T Seppälä
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Richard A Burkhart
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Peter J Espenshade
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Giovanis Institute for Translational Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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7
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Kubota CS, Myers SL, Seppälä TT, Burkhart RA, Espenshade PJ. In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.03.592368. [PMID: 38746286 PMCID: PMC11092789 DOI: 10.1101/2024.05.03.592368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. Using parallel in vitro and in vivo CRISPR knockout screens, we identified terpenoid backbone biosynthesis genes as essential for pancreatic ductal adenocarcinoma (PDAC) tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that geranylgeranyl diphosphate synthase 1 ( GGPS1 ) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model. These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
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8
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Ruze R, Song J, Yin X, Chen Y, Xu R, Wang C, Zhao Y. Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review. Signal Transduct Target Ther 2023; 8:139. [PMID: 36964133 PMCID: PMC10039087 DOI: 10.1038/s41392-023-01376-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/31/2023] [Accepted: 02/15/2023] [Indexed: 03/26/2023] Open
Abstract
Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
- Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
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Ruze R, Chen Y, Xu R, Song J, Yin X, Wang C, Xu Q. Obesity, diabetes mellitus, and pancreatic carcinogenesis: Correlations, prevention, and diagnostic implications. Biochim Biophys Acta Rev Cancer 2023; 1878:188844. [PMID: 36464199 DOI: 10.1016/j.bbcan.2022.188844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/13/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022]
Abstract
The prevalence of obesity, diabetes mellitus (DM), and pancreatic cancer (PC) has been consistently increasing in the last two decades worldwide. Sharing various influential risk factors in genetics and environmental inducers in pathogenesis, the close correlations of these three diseases have been demonstrated in plenty of clinical studies using multiple parameters among different populations. On the contrary, most measures aimed to manage and treat obesity and DM effectively reduce the risk and prevent PC occurrence, yet certain drugs can inversely promote pancreatic carcinogenesis instead. Most importantly, an elevation of blood glucose with or without a reduction in body weight, along with other potential tools, may provide valuable clues for detecting PC at an early stage in patients with obesity and DM, favoring a timely intervention and prolonging survival. Herein, the epidemiological and etiological correlations among these three diseases and the supporting clinical evidence of their connections are first summarized to favor a better and more thorough understanding of obesity- and DM-related pancreatic carcinogenesis. After comparing the distinct impacts of different weight-lowering and anti-diabetic treatments on the risk of PC, the possible diagnostic implications of hyperglycemia and weight loss in PC screening are also addressed in detail.
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Affiliation(s)
- Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China; Chinese Academy of Medical Sciences and Peking Union Medical College, No. 9 Dongdan Santiao, Beijing, China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China.
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Wangfujing Street, Beijing, China.
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Ejam SS, Saleh RO, Catalan Opulencia MJ, Najm MA, Makhmudova A, Jalil AT, Abdelbasset WK, Al-Gazally ME, Hammid AT, Mustafa YF, Sergeevna SE, Karampoor S, Mirzaei R. Pathogenic role of 25-hydroxycholesterol in cancer development and progression. Future Oncol 2022; 18:4415-4442. [PMID: 36651359 DOI: 10.2217/fon-2022-0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [Indexed: 01/19/2023] Open
Abstract
Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.
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Affiliation(s)
| | - Raed Obaid Saleh
- Department of Pharmacy, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Mazin Aa Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Aziza Makhmudova
- Department of Social Sciences & Humanities, Samarkand State Medical Institute, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, 100047, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health & Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sergushina Elena Sergeevna
- National Research Ogarev Mordovia State University, 68 Bolshevitskaya Street, Republic of Mordovia, Saransk, 430005, Russia
| | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom & Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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11
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Yin X, Xu R, Song J, Ruze R, Chen Y, Wang C, Xu Q. Lipid metabolism in pancreatic cancer: emerging roles and potential targets. CANCER COMMUNICATIONS (LONDON, ENGLAND) 2022; 42:1234-1256. [PMID: 36107801 PMCID: PMC9759769 DOI: 10.1002/cac2.12360] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 07/05/2022] [Accepted: 08/05/2022] [Indexed: 01/25/2023]
Abstract
Pancreatic cancer is one of the most serious health issues in developed and developing countries, with a 5-year overall survival rate currently <9%. Patients typically present with advanced disease due to vague symptoms or lack of screening for early cancer detection. Surgical resection represents the only chance for cure, but treatment options are limited for advanced diseases, such as distant metastatic or locally progressive tumors. Although adjuvant chemotherapy has improved long-term outcomes in advanced cancer patients, its response rate is low. So, exploring other new treatments is urgent. In recent years, increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage, and catabolism. Therefore, a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis, prognosis estimation, and targeted therapy for pancreatic cancer patients. In this review, we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer. In addition, we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer. Finally, we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.
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Affiliation(s)
- Xinpeng Yin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Jianlu Song
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Yuan Chen
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijing100023P. R China
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12
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Kim DS, Kim HJ, Ahn HS. Statins and the risk of gastric, colorectal, and esophageal cancer incidence and mortality: a cohort study based on data from the Korean national health insurance claims database. J Cancer Res Clin Oncol 2022; 148:2855-2865. [PMID: 35660949 DOI: 10.1007/s00432-022-04075-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 05/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND This study investigated the association between the use of statins, the incidence of gastric, colorectal, and esophageal cancers, and mortality between January 2005 and June 2013 in South Korea. METHODS We compared patients aged 45-70 years statin users for at least 6 months to non-statin users matched by age and sex, from 2004 to June 2013 using the National Health Insurance database. Main outcomes were gastric, colorectal, and esophageal cancer incidence and mortality. Cox proportional hazard regression was used to calculate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) among overall cohort and matched cohort after propensity score matching with a 1:1 ratio. RESULTS Out of 1,008,101 people, 20,473 incident cancers, 3938 cancer deaths occurred and 7669 incident cancer, 1438 cancer death in matched cohort. The aHRs for the association between the risk of cancers and statin use were 0.7 (95% CI 0.65-0.74) for gastric cancer, 0.73 (95% CI 0.69-0.78) for colorectal cancer, and 0.55 (95% CI 0.43-0.71) for esophageal cancer. There were associations between statin use and decreased gastric cancer mortality (HR 0.46, 95% CI 0.52-0.57), colorectal cancer mortality (HR 0.43, 95% CI 0.36-0.51), and esophageal cancer mortality (HR 0.41, 95% CI 0.27-0.50) in the overall cohort and this pattern was similar in the matched cohort. DISCUSSION Statin use for at least 6 months was significantly associated with a lower risk of stomach, colorectal, and esophageal cancer incidence as well as cancer mortality after a diagnosis.
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Affiliation(s)
- Dong-Sook Kim
- Department of Research, Health Insurance Review and Assessment Service, Wonju, Republic of Korea
| | - Hyun Jung Kim
- Department of Preventive Medicine, College of Medicine, Korea University, 126-1, 5-ga, Anam-dong, Sungbuk-gu, Seoul, 136-705, Republic of Korea
| | - Hyeong Sik Ahn
- Department of Preventive Medicine, College of Medicine, Korea University, 126-1, 5-ga, Anam-dong, Sungbuk-gu, Seoul, 136-705, Republic of Korea.
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13
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Miyaki C, Lynch LM. An Update on Common Pharmaceuticals in the Prevention of Pancreatic Cancer. Cureus 2022; 14:e25496. [PMID: 35800820 PMCID: PMC9246430 DOI: 10.7759/cureus.25496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2022] [Indexed: 01/03/2023] Open
Abstract
In this review, we aim to update readers about the most recent studies on common pharmaceuticals and their association with pancreatic cancer risk. The use of prophylactic aspirin, metformin, beta-blockers, and statins has been studied in the past but showed inconclusive results in the reduction of pancreatic cancer incidence. However, in recent studies, these medications along with combination therapy of aspirin and metformin were found to have a more significant association with decreasing risk. Given the poor prognosis of pancreatic cancer despite treatment, medication prophylaxis prevention should be considered. In this review, we hope to encourage future case-control or prospective studies on common medications that have shown great potential in delaying pancreatic cancer development.
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14
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Hayashi H, Uemura N, Zhao L, Matsumura K, Sato H, Shiraishi Y, Baba H. Biological Significance of YAP/TAZ in Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:700315. [PMID: 34395269 PMCID: PMC8358930 DOI: 10.3389/fonc.2021.700315] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 07/12/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer. Despite major advances in defining the molecular mutations driving PDAC, this disease remains universally lethal with an overall 5-year survival rate of only about 7–8%. Genetic alterations in PDAC are exemplified by four critical genes (KRAS, TP53, CDKN2A, and SMAD4) that are frequently mutated. Among these, KRAS mutation ranges from 88% to 100% in several studies. Hippo signaling is an evolutionarily conserved network that plays a key role in normal organ development and tissue regeneration. Its core consists of the serine/threonine kinases mammalian sterile 20-like kinase 1 and 2 (MST1/2) and large tumor suppressor 1 and 2. Interestingly, pancreas-specific MST1/2 double knockout mice have been reported to display a decreased pancreas mass. Many of the genes involved in the Hippo signaling pathway are recognized as tumor suppressors, while the Hippo transducers Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are identified as oncogenes. By dephosphorylation, YAP and TAZ accumulate in the nucleus and interact with transcription factors such as TEA domain transcription factor-1, 2, 3, and 4. Dysregulation of Hippo signaling and activation of YAP/TAZ have been recognized in a variety of human solid cancers, including PDAC. Recent studies have elucidated that YAP/TAZ play a crucial role in the induction of acinar-to-ductal metaplasia, an initial step in the progression to PDAC, in genetically engineered mouse models. YAP and TAZ also play a key role in the development of PDAC by both KRAS-dependent and KRAS-independent bypass mechanisms. YAP/TAZ have become extensively studied in PDAC and their biological importance during the development and progression of PDAC has been uncovered. In this review, we summarize the biological significance of a dysregulated Hippo signaling pathway or activated YAP/TAZ in PDAC and propose a role for YAP/TAZ as a therapeutic target.
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Affiliation(s)
- Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Liu Zhao
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuki Matsumura
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroki Sato
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuta Shiraishi
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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15
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Saito K, Sato Y, Nakatani E, Kaneda H, Yamamoto S, Miyachi Y, Itoh H. Statin Exposure and Pancreatic Cancer Incidence: A Japanese Regional Population-Based Cohort Study, the Shizuoka Study. Cancer Prev Res (Phila) 2021; 14:863-872. [PMID: 34244151 DOI: 10.1158/1940-6207.capr-21-0123] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 05/07/2021] [Accepted: 06/24/2021] [Indexed: 12/24/2022]
Abstract
Preclinical studies suggest that statins contribute to the prevention of pancreatic cancer; however, the results of epidemiologic studies are inconsistent. Furthermore, sufficient data are unavailable for the general population of Asia. Here, we conducted an observational study using a comprehensive patient-linked, longitudinal health insurance database comprising the records of 2,230,848 individuals residing in Shizuoka Prefecture, Japan, from April 2012 to September 2018. We included individuals older than 40 years with data for medical examinations and statin exposure (≥365 statin prescription days). To balance baseline characteristics between the statin exposure and statin nonexposure groups, we used inverse probability of treatment propensity score weighting method. We estimated hazard ratios for associations with pancreatic cancer using the Cox proportional hazards regression model. Among 2,230,848 individuals, we included 100,537 in the statin exposure group (24%) and 326,033 in the statin nonexposure group (76%). Among the statin exposure group (352,485 person-years) and the statin nonexposure group (1,098,463 person-years), 394 (1.12 per 1,000 person-years) and 1176 (1.07 per 1,000 person-years) developed pancreatic cancer, respectively (P = 0.464). After adjustments using inverse probability of treatment weighting, the statin exposure group was associated with a decreased incidence of pancreatic cancer (hazard ratio, 0.84; 95% confidence intervals, 0.72-0.99; P = 0.036). In conclusion, the current Japanese regional population-based cohort study shows that statin exposure was associated with a lower incidence of pancreatic cancer. PREVENTION RELEVANCE: This study may support the possible role of statins in preventing pancreatic cancer in the general population in Japan.
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Affiliation(s)
- Kohei Saito
- Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan.,Department of Endocrinology, Metabolism and Nephrology, School of Medicine, Keio University, Tokyo, Japan.,Shizuoka Graduate University of Public Health, Shizuoka City, Shizuoka, Japan
| | - Yoko Sato
- Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan.,Shizuoka Graduate University of Public Health, Shizuoka City, Shizuoka, Japan
| | - Eiji Nakatani
- Shizuoka General Hospital, Shizuoka City, Shizuoka, Japan. .,Shizuoka Graduate University of Public Health, Shizuoka City, Shizuoka, Japan
| | - Hideaki Kaneda
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe city, Hyogo, Japan
| | - Seiichiro Yamamoto
- Shizuoka Graduate University of Public Health, Shizuoka City, Shizuoka, Japan.,Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan
| | - Yoshiki Miyachi
- Shizuoka Graduate University of Public Health, Shizuoka City, Shizuoka, Japan
| | - Hiroshi Itoh
- Department of Endocrinology, Metabolism and Nephrology, School of Medicine, Keio University, Tokyo, Japan
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16
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Khalaf N, El-Serag HB, Abrams HR, Thrift AP. Burden of Pancreatic Cancer: From Epidemiology to Practice. Clin Gastroenterol Hepatol 2021; 19:876-884. [PMID: 32147593 PMCID: PMC8559554 DOI: 10.1016/j.cgh.2020.02.054] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 02/05/2020] [Accepted: 02/28/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide with 432,242 related deaths in 2018. Unlike other cancers, the incidence of pancreatic cancer continues to increase, with little improvement in survival rates. We review the epidemiologic features of pancreatic cancer, covering surveillance and early detection in high-risk persons. We summarize data on worldwide incidence and mortality and analyze the 1975-2016 data from 9 registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results study, on the overall burden of pancreatic cancer as well as age-, sex-, and race-specific incidence, survival rates and trends. It is important to increase our knowledge of the worldwide and regional epidemiologic features of and risk factors for pancreatic cancer, to identify new approaches for prevention, surveillance, and treatment.
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Affiliation(s)
- Natalia Khalaf
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas.
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Hannah R Abrams
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
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17
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Cholesterol Activates Cyclic AMP Signaling in Metaplastic Acinar Cells. Metabolites 2021; 11:metabo11030141. [PMID: 33652890 PMCID: PMC7996857 DOI: 10.3390/metabo11030141] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 02/06/2023] Open
Abstract
Cholesterol is a non-essential metabolite that exerts both structural and signaling functions. However, cholesterol biosynthesis is elevated, and actively supports, pancreatic carcinogenesis. Our previous work showed that statins block the reprogramming of mutant KRAS-expressing acinar cells, that spontaneously undergo a metaplastic event termed acinar-to-ductal metaplasia (ADM) to initiate carcinogenesis. Here we tested the impact of cholesterol supplementation on isolated primary wild-type acinar cells and observed enhanced ductal transdifferentiation, associated with generation of the second messenger cyclic adenosine monophosphate (cAMP) and the induction of downstream protein kinase A (PKA). Inhibition of PKA suppresses cholesterol-induced ADM ex vivo. Live imaging using fluorescent biosensors dissected the temporal and spatial dynamics of PKA activation upon cholesterol addition and showed uneven activation both in the cytosol and on the outer mitochondrial membrane of primary pancreatic acinar cells. The ability of cholesterol to activate cAMP signaling is lost in tumor cells. Qualitative examination of multiple normal and transformed cell lines supports the notion that the cAMP/PKA axis plays different roles during multi-step pancreatic carcinogenesis. Collectively, our findings describe the impact of cholesterol availability on the cyclic AMP/PKA axis and plasticity of pancreatic acinar cells.
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18
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Juarez D, Fruman DA. Targeting the Mevalonate Pathway in Cancer. Trends Cancer 2021; 7:525-540. [PMID: 33358111 DOI: 10.1016/j.trecan.2020.11.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 02/06/2023]
Abstract
The mevalonate synthesis inhibitors, statins, are mainstay therapeutics for cholesterol management and cardiovascular health. Thirty years of research have uncovered supportive roles for the mevalonate pathway in numerous cellular processes that support oncogenesis, most recently macropinocytosis. Central to the diverse mechanisms of statin sensitivity is an acquired dependence on one mevalonate pathway output, protein geranylgeranylation. New chemical prenylation probes and the discovery of a novel geranylgeranyl transferase hold promise to deepen our understanding of statin mechanisms of action. Further, insights into statin selection and the counterproductive role of dietary geranylgeraniol highlight how we should assess statins in the clinic. Lastly, rational combination strategies preview how statins will enter the oncology toolbox.
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Affiliation(s)
- Dennis Juarez
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA
| | - David A Fruman
- Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
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19
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Chen C, Wu H, Kong D, Xu Y, Zhang Z, Chen F, Zou L, Li Z, Shui J, Luo H, Liu SH, Yu J, Wang K, Brunicardi FC. Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer. Oncol Rep 2020; 44:2569-2580. [PMID: 33125137 PMCID: PMC7640361 DOI: 10.3892/or.2020.7810] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 09/15/2020] [Indexed: 12/20/2022] Open
Abstract
Statins, a class of commonly prescribed cholesterol‑lowering medications, have been revealed to influence the risk of multiple types of cancer. However, the antitumor effects of statins on pancreatic cancer and their differential efficacy among a variety of statins are not currently well‑defined. The aim of the present study was therefore to identify and compare the genes and related biological pathways that were affected by each individual statin on pancreatic cancer. Two human pancreatic cancer cell lines, MiaPaCa2 and PANC1, were exposed to three statins, lovastatin, fluvastatin and simvastatin. The inhibitory effect of statins on pancreatic cancer cell proliferation was first validated. Next, RNA‑seq analysis was used to determine the gene expression alterations in either low (2 µM) or high (20 µM) statin concentration‑treated cancer cells. Marked differences in gene transcription profiles of both pancreatic cancer cell lines exposed to high concentration statins were observed. Notably, the high concentration statins significantly suppressed core‑gene CCNA2‑associated cell cycle and DNA replication pathways and upregulated genes involved in ribosome and autophagy pathways. However, the low concentration statin‑induced gene expression alterations were only detected in MiaPaCa2 cells. In conclusion, a marked difference in the intra and inter cell‑type performance of pancreatic cancer cells exposed to a variety of statins at low or high concentrations was reported herein, which may provide insights for the potential clinical use of statins in future pancreatic cancer therapeutics.
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Affiliation(s)
- Cheng Chen
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Hongjin Wu
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Deshengyue Kong
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Yu Xu
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Zunyue Zhang
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Fengrong Chen
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Lei Zou
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Ziwei Li
- Shanghai International Travel Healthcare Center, Shanghai 200000, P.R. China
| | - Jin Shui
- Shanghai International Travel Healthcare Center, Shanghai 200000, P.R. China
| | - Huayou Luo
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - Shi-He Liu
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Juehua Yu
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
| | - Kunhua Wang
- The NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
| | - F. Charles Brunicardi
- Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA
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20
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Regular Statin Use and Incidence of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis. J Clin Gastroenterol 2020; 54:905-910. [PMID: 31895166 DOI: 10.1097/mcg.0000000000001312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
GOALS AND BACKGROUND Endoscopic retrograde cholangiopancreatography is widely utilized to diagnose and treat various pancreaticobiliary diseases, but postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) can be a fatal adverse event. Evidence suggests that statins may exhibit suppressive effects on inflammation in the pancreas. We carried out an observational cohort study to examine the protective effect of statins on PEP. STUDY We retrospectively identified consecutive patients who underwent endoscopic retrograde cholangiopancreatography at a tertiary care center in Japan between January 2010 and January 2019. The incidences of PEP were compared between regular and nonregular statin users. Using the multivariable logistic regression model, we examined the association of regular statin use with the incidence of PEP controlling for potential risk factors for PEP. RESULTS We included 2664 patients (328 regular statin users and 2336 nonregular users). The incidence of PEP did not differ by statin use status (P=0.52): 8.8% in regular statin users and 7.9% in nonregular users. The multivariable-adjusted odds ratio for PEP comparing regular statin use with nonregular use was 1.08 (95% confidence interval, 0.67-1.72; P=0.76). When we examined specific statin types (hydrophilic and lipophilic statins), we consistently observed the null association: 6.8% of 132 hydrophilic statin users and 10% of 196 lipophilic statin users (P=0.74 and 0.27, respectively, compared with nonregular users). CONCLUSIONS Regular statin use was not shown to be protective against PEP. A further investigation is warranted before this medication is tested in prospective randomized trials.
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21
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Matusewicz L, Czogalla A, Sikorski AF. Attempts to use statins in cancer therapy: An update. Tumour Biol 2020; 42:1010428320941760. [PMID: 32662332 DOI: 10.1177/1010428320941760] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Although it could be speculated that almost everything has been said concerning the use of statins in cancer therapy, statins as anticancer drugs have both committed supporters and opponents, for whom the dispute about the legitimacy of statin use in cancer treatment seems never to be clearly resolved; every year more than 300 reports which deepen the knowledge about statins and their influence on cancer cells are published. In this mini-review, we focus on the latest (since 2015) outcomes of cohort studies and meta-analyses indicating statin effectiveness in cancer treatment. We discuss attempts to improve the bioavailability of statins using nanocarriers and review the effectiveness of statins in combined therapies. We also summarise the latest results regarding the development of mechanisms of resistance to statins by cancer cells and, on the other hand, give a few examples where statins could potentially be used to overcome resistance to commonly used chemotherapeutics. Finally, special attention is paid to new reports on the effect of statins on epithelial-mesenchymal transition.
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Affiliation(s)
- Lucyna Matusewicz
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Aleksander Czogalla
- Department of Cytobiochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
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22
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Oni TE, Biffi G, Baker LA, Hao Y, Tonelli C, Somerville TD, Deschênes A, Belleau P, Hwang CI, Sánchez-Rivera FJ, Cox H, Brosnan E, Doshi A, Lumia RP, Khaledi K, Park Y, Trotman LC, Lowe SW, Krasnitz A, Vakoc CR, Tuveson DA. SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. J Exp Med 2020; 217:151922. [PMID: 32633781 PMCID: PMC7478739 DOI: 10.1084/jem.20192389] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 03/28/2020] [Accepted: 05/12/2020] [Indexed: 12/31/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol. Genetic targeting of Soat1 impairs cell proliferation in vitro and tumor progression in vivo and reveals a mevalonate pathway dependency in p53 mutant PDAC cells that have undergone p53 loss of heterozygosity (LOH). In contrast, pancreatic organoids lacking p53 mutation and p53 LOH are insensitive to SOAT1 loss, indicating a potential therapeutic window for inhibiting SOAT1 in PDAC.
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Affiliation(s)
- Tobiloba E. Oni
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY
| | - Giulia Biffi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Lindsey A. Baker
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Yuan Hao
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Claudia Tonelli
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Astrid Deschênes
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Chang-il Hwang
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Department of Microbiology and Molecular Genetics, University of California, Davis, Davis, CA
| | | | - Hilary Cox
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Erin Brosnan
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Abhishek Doshi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Rebecca P. Lumia
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Kimia Khaledi
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | - Youngkyu Park
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY
| | | | - Scott W. Lowe
- Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY,Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
| | | | | | - David A. Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY,Correspondence to David A. Tuveson:
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Lai SW, Kuo YH, Liao KF. Statins and pancreatic cancer risk. J Gastroenterol 2020; 55:471-472. [PMID: 32036452 DOI: 10.1007/s00535-020-01675-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 01/29/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Shih-Wei Lai
- College of Medicine, China Medical University, Taichung, Taiwan. .,Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan.
| | - Yu-Hung Kuo
- Department of Research, Taichung Tzu Chi Hospital, Taichung, Taiwan
| | - Kuan-Fu Liao
- College of Medicine, Tzu Chi University, Hualien, Taiwan.,Division of Hepatogastroenterology, Department of Internal Medicine, Taichung Tzu Chi Hospital, No. 66, Sec. 1, Fongsing Road, Tanzi District, Taichung City, 427, Taiwan
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24
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Hamada T, Ogino S, Wolpin BM. Response to the letter by Lai et al. regarding our manuscript "Statin use and pancreatic cancer risk in two prospective cohort studies". J Gastroenterol 2020; 55:473-474. [PMID: 32060759 PMCID: PMC7255069 DOI: 10.1007/s00535-020-01676-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
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26
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Garg S, Mardini H. Factors Related to Development of Pancreatic Adenocarcinoma in Patients With Chronic Pancreatitis on Long-term Follow-up: A Database Study. Perm J 2019; 24:18.211. [PMID: 31852038 PMCID: PMC6907905 DOI: 10.7812/tpp/18.211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND Chronic pancreatitis (CP) is a risk factor for pancreatic adenocarcinoma (PA). However, little is known about factors related to development of PA in CP. OBJECTIVE To evaluate factors associated with PA in CP. METHODS A national insurance database of 120 million US patients was used. Adults with an International Classification of Diseases, Ninth Revision (ICD-9) code for CP (577.1) from January 1, 2009, to December 31, 20014, were identified. Patients' age, sex, and ICD-9 codes for PA, bile duct obstruction, alcohol use, diabetes mellitus before and after diagnosis of CP, obesity, tobacco use, and type of insurance were obtained. Patients with CP without a unique identification number, missing dates for insurance coverage period, and with duration to end of follow-up or development of PA less than 2 years were excluded. The Cox proportional hazards regression model was used for analysis. RESULTS The final analysis had 30,555 patients with CP including 219 patients (0.72%) with PA. The Cox proportional hazards regression model showed that in patients with CP age (hazard ratio [HR] = 1.07; 95% Confidence Interval [CI] = 1.03-1.1), male sex (HR = 2.1; 95% CI = 1.25-3.54), tobacco use (HR = 1.88; 95% CI = 1.1-3.23), and having commercial insurance (HR = 4.26; 95% CI = 1.63-11.11) were associated with a subsequent medical claim for PA. Duration of bile duct obstruction (HR = 0.999; 95% CI = 0.998-0.999) and presence of diabetes mellitus before CP (HR = 0.35; 95% CI = 0.19-0.63) were inversely related to subsequent diagnosis of PA. CONCLUSION PA was diagnosed in 0.72% of the patients with CP at least 2 years after the diagnosis of CP. Increasing age, male sex, tobacco use, having commercial insurance, absence of diabetes mellitus before CP, and shorter duration of bile duct obstruction were associated with a diagnosis of PA in patients with CP.
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Affiliation(s)
- Shashank Garg
- Division of Gastroenterology, College of Medicine, University of Arkansas, Little Rock
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington
| | - Houssam Mardini
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington
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Hamada T, Yuan C, Bao Y, Zhang M, Khalaf N, Babic A, Morales-Oyarvide V, Cochrane BB, Gaziano JM, Giovannucci EL, Kraft P, Manson JE, Ng K, Nowak JA, Rohan TE, Sesso HD, Stampfer MJ, Amundadottir LT, Fuchs CS, De Vivo I, Ogino S, Wolpin BM. Prediagnostic Leukocyte Telomere Length and Pancreatic Cancer Survival. Cancer Epidemiol Biomarkers Prev 2019; 28:1868-1875. [PMID: 31427306 PMCID: PMC6825575 DOI: 10.1158/1055-9965.epi-19-0577] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/12/2019] [Accepted: 08/13/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Leukocyte telomere length has been associated with risk of subsequent pancreatic cancer. Few prospective studies have evaluated the association of prediagnostic leukocyte telomere length with pancreatic cancer survival. METHODS We prospectively examined the association of prediagnostic leukocyte telomere length with overall survival (OS) time among 423 participants diagnosed with pancreatic adenocarcinoma between 1984 and 2008 within the Health Professionals Follow-up Study, Nurses' Health Study, Physicians' Health Study, and Women's Health Initiative. We measured prediagnostic leukocyte telomere length in banked blood samples using quantitative PCR. Cox proportional hazards models were used to estimate HRs for OS with adjustment for potential confounders. We also evaluated 10 SNPs at the telomerase reverse transcriptase locus. RESULTS Shorter prediagnostic leukocyte telomere length was associated with reduced OS among patients with pancreatic cancer (P trend = 0.04). The multivariable-adjusted HR for OS comparing the lowest with highest quintiles of leukocyte telomere length was 1.39 (95% confidence interval, 1.01-1.93), corresponding to a 3-month difference in median OS time. In an analysis excluding cases with blood collected within 2 years of cancer diagnosis, the association was moderately stronger (HR, 1.55; 95% confidence interval, 1.09-2.21; comparing the lowest with highest quintiles; P trend = 0.01). No prognostic association or effect modification for the prognostic association of prediagnostic leukocyte telomere length was noted in relation to the studied SNPs. CONCLUSIONS Prediagnostic leukocyte telomere length was associated with pancreatic cancer survival. IMPACT Prediagnostic leukocyte telomere length can be a prognostic biomarker in pancreatic cancer.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Ying Bao
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Mingfeng Zhang
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Natalia Khalaf
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Vicente Morales-Oyarvide
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | | | - J Michael Gaziano
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Jamaica Plain, Massachusetts
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - JoAnn E Manson
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Thomas E Rohan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Howard D Sesso
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Meir J Stampfer
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Laufey T Amundadottir
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Charles S Fuchs
- Yale Cancer Center, New Haven, Connecticut
- Department of Medicine, Yale School of Medicine, New Haven, Connecticut
- Smilow Cancer Hospital, New Haven, Connecticut
| | - Immaculata De Vivo
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
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28
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Choi JH, Lee SH, Huh G, Chun JW, You MS, Paik WH, Ryu JK, Kim YT. The association between use of statin or aspirin and pancreatic ductal adenocarcinoma: A nested case-control study in a Korean nationwide cohort. Cancer Med 2019; 8:7419-7430. [PMID: 31637875 PMCID: PMC6885885 DOI: 10.1002/cam4.2617] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 09/29/2019] [Accepted: 10/03/2019] [Indexed: 12/12/2022] Open
Abstract
Background Although several studies have suggested that aspirin and statins may help prevent pancreatic ductal adenocarcinoma (PDAC), this concept has been controversial. This study aimed to evaluate the association between use of statin or aspirin and PDAC in a nationwide large cohort. Methods In this nested case‐control study, we used data from a 12‐year nationwide longitudinal cohort in Korea. Cases with PDAC and controls who were matched to cases by age, sex, income, and index year at a 1:5 ratio were established. We used multivariate logistic regression analyses to identify the independent risk factors of PDAC. Results We identified a total of 827 patients with PDAC between 2007 and 2013, and included 4135 matched controls. Diabetes mellitus, chronic and acute pancreatitis, pancreatic cystic lesions, and cholelithiasis were independent risk factors for PDAC. Statin use (odds ratio [OR], 0.92; 95% confidence interval [CI] 0.76‐1.11; P = .344; adjusted OR [aOR], 0.70; 95% CI 0.56‐0.87; P = .001) was associated with a reduced risk of PDAC after correction of the confounding factors, but aspirin use (OR, 0.98; 95% CI 0.84‐1.15; P = .838; aOR 0.84; 95% CI 0.70‐1.01, P = .068) was not associated with PDAC. Among the patients with risk factors, both statin use (OR, 0.50; 95% CI 0.38‐0.66; P < .001; aOR, 0.62; 95% CI 0.45‐0.84; P = .002) and aspirin use (OR, 0.48; 95% CI 0.31‐0.67; P < .001; aOR 0.67; 95% CI 0.50‐0.89, P = .006) were associated with a reduced risk of PDAC. Conclusion This study suggests that statin use was associated with a reduced risk of PDAC incidence but aspirin use was not. Both statin use and aspirin use were associated a reduced risk of PDAC incidence for patients with risk factors.
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Affiliation(s)
- Jin Ho Choi
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Sang Hyub Lee
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gunn Huh
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung Won Chun
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Min Su You
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Woo Hyun Paik
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji Kon Ryu
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yong-Tae Kim
- Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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29
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Hao F, Xu Q, Wang J, Yu S, Chang HH, Sinnett-Smith J, Eibl G, Rozengurt E. Lipophilic statins inhibit YAP nuclear localization, co-activator activity and colony formation in pancreatic cancer cells and prevent the initial stages of pancreatic ductal adenocarcinoma in KrasG12D mice. PLoS One 2019; 14:e0216603. [PMID: 31100067 PMCID: PMC6524808 DOI: 10.1371/journal.pone.0216603] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 04/24/2019] [Indexed: 01/06/2023] Open
Abstract
We examined the impact of statins on Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. Exposure of sparse cultures of PANC-1 and MiaPaCa-2 cells to cerivastatin or simvastatin induced a striking re-localization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEAD-regulated genes Connective Tissue Growth Factor (CTGF) and Cysteine-rich angiogenic inducer 61 (CYR61). Statins also prevented YAP nuclear import and expression of CTGF and CYR61 stimulated by the mitogenic combination of insulin and neurotensin in dense culture of these PDAC cells. Cerivastatin, simvastatin, atorvastatin and fluvastatin also inhibited colony formation by PANC-1 and MiaPaCa-2 cells in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin did not exert any inhibitory effect even at a high concentration (10 μM). Mechanistically, cerivastatin did not alter the phosphorylation of YAP at Ser127 in either PANC-1 or MiaPaCa-2 cells incubated without or with neurotensin and insulin but blunted the assembly of actin stress fiber in these cells. We extended these findings with human PDAC cells using primary KC and KPC cells, (expressing KrasG12D or both KrasG12D and mutant p53, respectively) isolated from KC or KPC mice. Using cultures of these murine cells, we show that lipophilic statins induced striking YAP translocation from the nucleus to the cytoplasm, inhibited the expression of Ctgf, Cyr61 and Birc5 and profoundly inhibited colony formation of these cells. Administration of simvastatin to KC mice subjected to diet-induced obesity prevented early pancreatic acini depletion and PanIN formation. Collectively, our results show that lipophilic statins restrain YAP activity and proliferation in pancreatic cancer cell models in vitro and attenuates early lesions leading to PDAC in vivo.
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Affiliation(s)
- Fang Hao
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Tianjin Medical University, Tianjin, China
| | - Qinhong Xu
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Xi'an Jiaotong University, Xi'an, China
| | - Jing Wang
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Xi'an Jiaotong University, Xi'an, China
| | - Shuo Yu
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- Xi'an Jiaotong University, Xi'an, China
| | - Hui-Hua Chang
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- CURE: Digestive Diseases Research Center, Los Angeles, California, United States of America
| | - James Sinnett-Smith
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- CURE: Digestive Diseases Research Center, Los Angeles, California, United States of America
- VA Greater Los Angeles Health Care System, Los Angeles, California, United States of America
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- CURE: Digestive Diseases Research Center, Los Angeles, California, United States of America
| | - Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
- CURE: Digestive Diseases Research Center, Los Angeles, California, United States of America
- VA Greater Los Angeles Health Care System, Los Angeles, California, United States of America
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30
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Primary and Secondary Prevention of Pancreatic Cancer. CURR EPIDEMIOL REP 2019. [DOI: 10.1007/s40471-019-00189-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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31
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Rozengurt E, Eibl G. Central role of Yes-associated protein and WW-domain-containing transcriptional co-activator with PDZ-binding motif in pancreatic cancer development. World J Gastroenterol 2019; 25:1797-1816. [PMID: 31057295 PMCID: PMC6478619 DOI: 10.3748/wjg.v25.i15.1797] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/20/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC. Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network. Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
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Affiliation(s)
- Enrique Rozengurt
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
| | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, United States
- CURE: Digestive Diseases Research Center, Los Angeles, CA 90095, United States
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32
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Carrer A, Trefely S, Zhao S, Campbell SL, Norgard RJ, Schultz KC, Sidoli S, Parris JLD, Affronti HC, Sivanand S, Egolf S, Sela Y, Trizzino M, Gardini A, Garcia BA, Snyder NW, Stanger BZ, Wellen KE. Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis. Cancer Discov 2019; 9:416-435. [PMID: 30626590 PMCID: PMC6643997 DOI: 10.1158/2159-8290.cd-18-0567] [Citation(s) in RCA: 218] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 12/03/2018] [Accepted: 01/04/2019] [Indexed: 12/13/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA-producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT-ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA-dependent processes exerts anticancer effects. SIGNIFICANCE: Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways.See related commentary by Halbrook et al., p. 326.This article is highlighted in the In This Issue feature, p. 305.
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Affiliation(s)
- Alessandro Carrer
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sophie Trefely
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania
| | - Steven Zhao
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sydney L Campbell
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert J Norgard
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Medicine, Gastroenterology Division, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kollin C Schultz
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Simone Sidoli
- Epigenetics Institute, Departments of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Joshua L D Parris
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hayley C Affronti
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sharanya Sivanand
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shaun Egolf
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Yogev Sela
- Department of Medicine, Gastroenterology Division, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Marco Trizzino
- The Wistar Institute, Gene Expression and Regulation Program, Philadelphia, Pennsylvania
| | - Alessandro Gardini
- The Wistar Institute, Gene Expression and Regulation Program, Philadelphia, Pennsylvania
| | - Benjamin A Garcia
- Epigenetics Institute, Departments of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Nathaniel W Snyder
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania
| | - Ben Z Stanger
- A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania
| | - Kathryn E Wellen
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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Abstract
OBJECTIVE The aim of this study was to explore the relationship between statin use and the risk of pancreatic cancer. METHODS Electronic databases were searched to identify relevant studies published until January 2018. The pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated with random-effects model. Subgroup analyses and sensitivity analysis were also conducted. Cochran Q test and I(2) statistic were used to evaluate the heterogeneity. RESULTS Twenty-six studies were included that contained more than 3 million participants and 170,000 pancreatic cancer patients. The overall result demonstrated a significant decrease in pancreatic cancer risk with statin use (RR, 0.84; 95% CI, 0.73-0.97; P = 0.000; I(2) = 84.4%). In subgroup analyses, nonsignificant association was detected between long-term statin use and the risk of pancreatic cancer (RR, 0.98; 95% CI, 0.86-1.11; P = 0.718; I(2) = 0.0%). Meanwhile, there was nonsignificant association between the use of lipophilic statins and the risk of pancreatic cancer (RR, 0.98; 95% CI, 0.84-1.15; P = 0.853; I(2) = 27.2%). No publication bias was found in this meta-analysis. CONCLUSIONS The overall result of this meta-analysis supports the hypothesis that statins have a protective effect on pancreatic cancer. Furthermore, high-quality randomized clinical trials and cohort studies are needed to confirm these findings.
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Mo H, Jeter R, Bachmann A, Yount ST, Shen CL, Yeganehjoo H. The Potential of Isoprenoids in Adjuvant Cancer Therapy to Reduce Adverse Effects of Statins. Front Pharmacol 2019; 9:1515. [PMID: 30662405 PMCID: PMC6328495 DOI: 10.3389/fphar.2018.01515] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 12/11/2018] [Indexed: 12/11/2022] Open
Abstract
The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), “mixed” isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy.
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Affiliation(s)
- Huanbiao Mo
- Department of Nutrition, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University, Atlanta, GA, United States
| | - Rayna Jeter
- Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Andrea Bachmann
- Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Sophie T Yount
- Department of Chemistry, Georgia State University, Atlanta, GA, United States
| | - Chwan-Li Shen
- Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Hoda Yeganehjoo
- Department of Clinical Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, United States
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Kovač U, Skubic C, Bohinc L, Rozman D, Režen T. Oxysterols and Gastrointestinal Cancers Around the Clock. Front Endocrinol (Lausanne) 2019; 10:483. [PMID: 31379749 PMCID: PMC6653998 DOI: 10.3389/fendo.2019.00483] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 07/03/2019] [Indexed: 12/24/2022] Open
Abstract
This review focuses on the role of oxidized sterols in three major gastrointestinal cancers (hepatocellular carcinoma, pancreatic, and colon cancer) and how the circadian clock affects the carcinogenesis by regulating the lipid metabolism and beyond. While each field of research (cancer, oxysterols, and circadian clock) is well-studied within their specialty, little is known about the intertwining mechanisms and how these influence the disease etiology in each cancer type. Oxysterols are involved in pathology of these cancers, but final conclusions about their protective or damaging effects are elusive, since the effect depends on the type of oxysterol, concentration, and the cell type. Oxysterol concentrations, the expression of key regulators liver X receptors (LXR), farnesoid X receptor (FXR), and oxysterol-binding proteins (OSBP) family are modulated in tumors and plasma of cancer patients, exposing these proteins and selected oxysterols as new potential biomarkers and drug targets. Evidence about how cholesterol/oxysterol pathways are intertwined with circadian clock is building. Identified key contact points are different forms of retinoic acid receptor related orphan receptors (ROR) and LXRs. RORs and LXRs are both regulated by sterols/oxysterols and the circadian clock and in return also regulate the same pathways, representing a complex interplay between sterol metabolism and the clock. With this in mind, in addition to classical therapies to modulate cholesterol in gastrointestinal cancers, such as the statin therapy, the time is ripe also for therapies where time and duration of the drug application is taken as an important factor for successful therapies. The final goal is the personalized approach with chronotherapy for disease management and treatment in order to increase the positive drug effects.
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Archibugi L, Arcidiacono PG, Capurso G. Statin use is associated to a reduced risk of pancreatic cancer: A meta-analysis. Dig Liver Dis 2019; 51:28-37. [PMID: 30314951 DOI: 10.1016/j.dld.2018.09.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous studies investigating the association between statin use and pancreatic cancer (PDAC) risk for a possible chemopreventive effect gathered heterogeneous results. AIMS To conduct a systematic review and meta-analysis to clarify this association. METHODS Comprehensive literature search of articles published up to February 2018, including case-control (CC),cohort studies (C), randomized controlled trials (RCTs) assessing association between statin use and PDAC risk. Studies had to report odds ratio (OR)/relative risk (RR), estimates with 95% confidence interval (CI), or provide data for their calculation. Pooled ORs with 95%CIs were calculated using random effects model, publication bias through Begg and Mazumdar test and heterogeneity by I2 value. RESULTS 27 studies(13 CC, 9C, 5 RCTs) for a total population of 11,975 PDAC/3,433,175 controls contributed to the analysis. The overall pooled result demonstrated a reduced PDAC risk among statin users (OR 0.70; 95% CI 0.60-0.82; p < 0.0001), compared to non-users. Sensitivity analyses suggested the risk reduction to be more important in CC studies, studies conducted in Asia and Europe, in males and atorvastatin users. No publication bias found. CONCLUSIONS The present meta-analysis suggests that statin use is associated with an overall PDAC risk reduction of 30%. Further studies are needed to clarify the association.
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Affiliation(s)
- Livia Archibugi
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Paolo Giorgio Arcidiacono
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
| | - Gabriele Capurso
- Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy.
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Hamada T, Khalaf N, Yuan C, Morales-Oyarvide V, Babic A, Nowak JA, Qian ZR, Ng K, Rubinson DA, Kraft P, Giovannucci EL, Stampfer MJ, Fuchs CS, Ogino S, Wolpin BM. Prediagnosis Use of Statins Associates With Increased Survival Times of Patients With Pancreatic Cancer. Clin Gastroenterol Hepatol 2018; 16:1300-1306.e3. [PMID: 29474971 PMCID: PMC6056316 DOI: 10.1016/j.cgh.2018.02.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/29/2018] [Accepted: 02/11/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Statin medications, most commonly prescribed to reduce lipid levels and prevent cardiovascular disease, may be associated with longer survival times of patients with cancer. However, the association of statins with outcomes of patients with pancreatic adenocarcinoma is not clear. METHODS We analyzed the association of statin use before a diagnosis of pancreatic cancer with survival times of 648 participants in the Nurses' Health Study and Health Professionals Follow-up Study who were diagnosed with pancreatic adenocarcinoma from 2000 through 2013. We estimated hazard ratios (HRs) for overall mortality using Cox proportional hazards models with adjustment for potential confounders. We assessed the temporal association between prediagnosis statin use and cancer survival by 2-year lag periods to account for a possible latency period between statin use and cancer survival. RESULTS Regular statin use before diagnosis of pancreatic cancer was associated with modestly prolonged survival compared with nonregular use (adjusted HR, 0.82; 95% CI, 0.69-0.97; P = .02). A 1-month longer median survival was observed in regular statin users compared with nonregular users. Regular statin use within the 2 years prior to cancer diagnosis was most strongly associated with longer survival. We observed no statistically significant effect modification by smoking status, body mass index, diabetes, or cancer stage (all Pinteraction > .53). Regular statin use before diagnosis was similarly associated with survival in the Nurses' Health Study (HR, 0.79; 95% CI, 0.64-0.97) and Health Professionals Follow-up Study (HR, 0.86; 95% CI, 0.63-1.15). CONCLUSIONS Regular statin use before diagnosis of pancreatic cancer was associated with modest increases in survival times in 2 large prospective cohort studies.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Natalia Khalaf
- Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Vicente Morales-Oyarvide
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Ana Babic
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Zhi Rong Qian
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Douglas A Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Peter Kraft
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Meir J Stampfer
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Charles S Fuchs
- Yale Cancer Center, New Haven, Connecticut; Department of Medicine, Yale School of Medicine, New Haven, Connecticut; Smilow Cancer Hospital, New Haven, Connecticut
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Brian M Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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