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Zou J, Shen YK, Wu SN, Wei H, Li QJ, Xu SH, Ling Q, Kang M, Liu ZL, Huang H, Chen X, Wang YX, Liao XL, Tan G, Shao Y. Prediction Model of Ocular Metastases in Gastric Adenocarcinoma: Machine Learning-Based Development and Interpretation Study. Technol Cancer Res Treat 2024; 23:15330338231219352. [PMID: 38233736 PMCID: PMC10865948 DOI: 10.1177/15330338231219352] [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: 11/30/2022] [Revised: 10/10/2023] [Accepted: 11/08/2023] [Indexed: 01/19/2024] Open
Abstract
Background: Although gastric adenocarcinoma (GA) related ocular metastasis (OM) is rare, its occurrence indicates a more severe disease. We aimed to utilize machine learning (ML) to analyze the risk factors of GA-related OM and predict its risks. Methods: This is a retrospective cohort study. The clinical data of 3532 GA patients were collected and randomly classified into training and validation sets in a ratio of 7:3. Those with or without OM were classified into OM and non-OM (NOM) groups. Univariate and multivariate logistic regression analyses and least absolute shrinkage and selection operator were conducted. We integrated the variables identified through feature importance ranking and further refined the selection process using forward sequential feature selection based on random forest (RF) algorithm before incorporating them into the ML model. We applied six ML algorithms to construct the predictive GA model. The area under the receiver operating characteristic (ROC) curve indicated the model's predictive ability. Also, we established a network risk calculator based on the best performance model. We used Shapley additive interpretation (SHAP) to identify risk factors and to confirm the interpretability of the black box model. We have de-identified all patient details. Results: The ML model, consisting of 13 variables, achieved an optimal predictive performance using the gradient boosting machine (GBM) model, with an impressive area under the curve (AUC) of 0.997 in the test set. Utilizing the SHAP method, we identified crucial factors for OM in GA patients, including LDL, CA724, CEA, AFP, CA125, Hb, CA153, and Ca2+. Additionally, we validated the model's reliability through an analysis of two patient cases and developed a functional online web prediction calculator based on the GBM model. Conclusion: We used the ML method to establish a risk prediction model for GA-related OM and showed that GBM performed best among the six ML models. The model may identify patients with GA-related OM to provide early and timely treatment.
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Affiliation(s)
- Jie Zou
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Yan-Kun Shen
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Shi-Nan Wu
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
- Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - Hong Wei
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Qing-Jian Li
- Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Eye Institute of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
| | - San Hua Xu
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Qian Ling
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Min Kang
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Zhao-Lin Liu
- Department of Ophthalmology, the First Affiliated Hospital of University of South China, Hunan Branch of National Clinical Research Center for Ocular Disease, Hengyan, Hunan Province, People's Republic of China
| | - Hui Huang
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
| | - Xu Chen
- Department of Ophthalmology and Visual Sciences, Maastricht University, Maastricht, Limburg Province, Netherlands
| | - Yi-Xin Wang
- School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Xu-Lin Liao
- Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People's Republic of China
| | - Gang Tan
- Department of Ophthalmology, the First Affiliated Hospital of University of South China, Hunan Branch of National Clinical Research Center for Ocular Disease, Hengyan, Hunan Province, People's Republic of China
| | - Yi Shao
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi Branch of National Clinical Research Center for Ocular Disease, Nanchang, Jiangxi, People's Republic of China
- Current affiliation: Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai, China
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Galvan GC, Friedrich NA, Das S, Daniels JP, Pollan S, Dambal S, Suzuki R, Sanders SE, You S, Tanaka H, Lee YJ, Yuan W, de Bono JS, Vasilevskaya I, Knudsen KE, Freeman MR, Freedland SJ. 27-hydroxycholesterol and DNA damage repair: implication in prostate cancer. Front Oncol 2023; 13:1251297. [PMID: 38188290 PMCID: PMC10771304 DOI: 10.3389/fonc.2023.1251297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 12/04/2023] [Indexed: 01/09/2024] Open
Abstract
Introduction We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects. Methods We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment analysis was done using the GSEA software with hallmark gene sets from MSigDB. Key changes were validated at mRNA and protein levels. Human PC transcriptomes from six datasets were analyzed to determine the correlation between CYP27A1 and DNA repair gene expression signatures. DNA damage was assessed via comet assays. Results Transcriptome analysis revealed 27HC treatment downregulated Hallmark pathways related to DNA damage repair, decreased expression of FEN1 and RAD51, and induced "BRCAness" by downregulating genes involved in homologous recombination regulation in LNCaP cells. Consistently, we found a correlation between higher CYP27A1 expression (i.e., higher intracellular 27HC) and decreased expression of DNA repair gene signatures in castration-sensitive PC (CSPC) in human PC datasets. However, such correlation was less clear in metastatic castration-resistant PC (mCRPC). 27HC increased expression of DNA damage repair markers in PC cells, notably in AR+ cells, but no consistent effects in AR- cells and decreased expression in non-neoplastic prostate epithelial cells. While testing the clinical implications of this, we noted that 27HC treatment increased DNA damage in LNCaP cells via comet assays. Effects were reversible by adding back cholesterol, but not androgens. Finally, in combination with olaparib, a PARP inhibitor, we showed additive DNA damage effects. Discussion These results suggest 27HC induces "BRCAness", a functional state thought to increase sensitivity to PARP inhibitors, and leads to increased DNA damage, especially in CSPC. Given the emerging appreciation that defective DNA damage repair can drive PC growth, future studies are needed to test whether 27HC creates a synthetic lethality to PARP inhibitors and DNA damaging agents in CSPC.
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Affiliation(s)
- Gloria Cecilia Galvan
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Nadine A. Friedrich
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Sanjay Das
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Urology, University of California, Los Angeles, Los Angeles, CA, United States
- Urology Section, Department of Surgery, Veterans Affairs Health Care System, Durham, NC, United States
| | - James P. Daniels
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Sara Pollan
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Shweta Dambal
- Department of Pathology, Duke University School of Medicine, Durham, NC, United States
| | - Ryusuke Suzuki
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Sergio E. Sanders
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Sungyong You
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Hisashi Tanaka
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Yeon-Joo Lee
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Wei Yuan
- Cancer Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
| | - Johann S. de Bono
- Cancer Biomarkers Team, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Prostate Cancer Targeted Therapy Group and Drug Development Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Irina Vasilevskaya
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, PA, United States
| | - Karen E. Knudsen
- Department of Cancer Biology at Thomas Jefferson University, Philadelphia, PA, United States
| | - Michael R. Freeman
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Stephen J. Freedland
- Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Urology Section, Department of Surgery, Veterans Affairs Health Care System, Durham, NC, United States
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Wang YH, Zhang SS, Li HT, Zhi HW, Wu HY. Rhabdomyolysis-induced acute kidney injury after administration of a red yeast rice supplement: A case report. World J Clin Cases 2023; 11:5547-5553. [PMID: 37637685 PMCID: PMC10450378 DOI: 10.12998/wjcc.v11.i23.5547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 06/17/2023] [Accepted: 07/17/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND A few reports have revealed induction of rhabdomyolysis by a red yeast rice (RYR) supplement or by RYR in combination with abiraterone (an androgen biosynthesis inhibitor). CASE SUMMARY A 76-year-old man presented with progressive limb weakness, muscle soreness, and acute kidney injury (AKI). He had been taking the anti-prostate cancer drug abiraterone for 14 mo and had added a RYR supplement 3 mo before symptom onset. After being diagnosed with rhabdomyolysis-induced AKI, the patient discontinued these drugs and responded well to hemodialysis and hemoperfusion. After 23 d of treatment, creatine kinase levels returned to normal and serum creatinine levels decreased. CONCLUSION We speculate that statins, the main lipid-lowering component of RYR, or a combination of statins and abiraterone, will increase the risk of rhabdomyolysis.
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Affiliation(s)
- Ya-Han Wang
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
| | - Si-Shuo Zhang
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
| | - Hai-Tao Li
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
| | - Hong-Wei Zhi
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
| | - Hong-Yun Wu
- Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
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Du Y, Wan H, Huang P, Yang J, He Y. A critical review of Astragalus polysaccharides: From therapeutic mechanisms to pharmaceutics. Pharmacotherapy 2022; 147:112654. [DOI: 10.1016/j.biopha.2022.112654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/09/2022] [Accepted: 01/16/2022] [Indexed: 12/12/2022]
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Lethongsavarn V, Pinault M, Diedhiou A, Guimaraes C, Guibon R, Bruyère F, Mathieu R, Rioux-Leclercq N, Multigner L, Brureau L, Fournier G, Doucet L, Blanchet P, Fromont G. Tissue cholesterol metabolism and prostate cancer aggressiveness: Ethno-geographic variations. Prostate 2021; 81:1365-1373. [PMID: 34516695 DOI: 10.1002/pros.24234] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/30/2021] [Indexed: 11/09/2022]
Abstract
BACKGROUND Prostate cancer (PCa) is more frequent and more aggressive in populations of African descent than in Caucasians. Since the fatty acid composition of peri-prostatic adipose tissue (PPAT) has been shown to differ according to the ethno-geographic origin and is involved in PCa aggressiveness, we aimed to analyze the cholesterol content of PPAT from Caucasian and African-Caribbean patients, in correlation with markers of disease aggressiveness and cholesterol metabolism in cancer tissues. METHODS The quantification of cholesterol in PPAT was analyzed in 52 Caucasian and 52 African-Caribbean PCa patients, with in each group 26 indolent tumors (ISUP Group1 and pT2) and 26 potentially aggressive tumors (ISUP Group 3-5 and/or pT3). The expression of proteins involved in cholesterol metabolism was analyzed by immunohistochemistry on cancer tissue samples included in tissue microarrays. RESULTS The amount of cholesterol esters was lower in PPAT from African-Caribbean patients compared with Caucasians, without any correlation with markers of disease aggressiveness. In cancer tissues from African-Caribbean patients, the expression of ABCA1 (involved in cholesterol efflux) was decreased, and that of SREBP-2 (involved in cholesterol uptake) was increased. In both groups of patients, SREBP-2 expression was strongly associated with that of Zeb1, a key player in the epithelial-to-mesenchymal transition (EMT) process. CONCLUSION These results suggest that cholesterol metabolism differs according to the ethno-geographic origin, in both PPAT and cancer tissues. In African-Caribbeans, the orientation towards accumulation of cholesterol in cancer cells is associated with a more frequent state of EMT, which may promote PCa aggressiveness in this population.
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Affiliation(s)
- Vincent Lethongsavarn
- Inserm UMR1069 "Nutrition, Croissance et Cancer", Université de Tours, Tours, France
- Department of Pathology, CHU de la Guadeloupe, Guadeloupe, France
- Department of Urology, Université des Antilles, Pointe-à-Pitre, France
| | - Michèle Pinault
- Inserm UMR1069 "Nutrition, Croissance et Cancer", Université de Tours, Tours, France
| | | | - Cyrille Guimaraes
- Inserm UMR1069 "Nutrition, Croissance et Cancer", Université de Tours, Tours, France
| | - Roseline Guibon
- Inserm UMR1069 "Nutrition, Croissance et Cancer", Université de Tours, Tours, France
- Department of Pathology, CHRU Tours, Tours, France
| | | | - Romain Mathieu
- Department of Urology, CHU Rennes, Rennes, France
- Inserm UMR1085 - IRSET, EHESP, Université de Rennes, Rennes, France
| | - Nathalie Rioux-Leclercq
- Inserm UMR1085 - IRSET, EHESP, Université de Rennes, Rennes, France
- Department of Pathology, CHU Rennes, Rennes, France
| | - Luc Multigner
- Inserm UMR1085 - IRSET, EHESP, Université de Rennes, Rennes, France
| | - Laurent Brureau
- Department of Urology, Université des Antilles, Pointe-à-Pitre, France
- Inserm UMR1085 - IRSET, EHESP, Université de Rennes, Rennes, France
- Department of Urology, CHU de la Guadeloupe, Pointe-à-Pitre, France
| | | | | | - P Blanchet
- Department of Urology, Université des Antilles, Pointe-à-Pitre, France
- Inserm UMR1085 - IRSET, EHESP, Université de Rennes, Rennes, France
- Department of Urology, CHU de la Guadeloupe, Pointe-à-Pitre, France
| | - Gaëlle Fromont
- Inserm UMR1069 "Nutrition, Croissance et Cancer", Université de Tours, Tours, France
- Department of Pathology, CHRU Tours, Tours, France
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Hirano H, Ide H, Lu Y, Inoue Y, Okada H, Horie S. Impact of Pretreatment Total Cholesterol Level Is Associated With Metastasis of Prostate Cancer. Am J Mens Health 2021; 14:1557988320918788. [PMID: 32349610 PMCID: PMC7233000 DOI: 10.1177/1557988320918788] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Metabolic syndrome is reported to play a role in the genesis and development not
only of angina, arteriosclerosis, diabetes, and osteoporosis but also of
prostate cancer. Hypercholesterolemia is a strong risk factor in prostate cancer
development. The current study was conducted to analyze whether pretreatment
serum levels of cholesterol correlate with prostate cancer metastasis. Three
hundred fifty-one subjects who received a histopathological diagnosis of
prostate cancer were evaluated by clinical factors such as age, body mass index
(BMI), disease stage, Gleason score, prostate-specific antigen (PSA), total
cholesterol, Luteinizing hormone (LH), testosterone, and free testosterone. A
multivariate analysis was performed on these factors, and a statistically
significant difference was identified in total cholesterol level
(p =.01) and PSA (p < .001). The total
cholesterol level was higher in cases of metastatic prostate cancer compared to
nonmetastatic prostate cancer in this study and therefore may be a predictive
factor for poor prognosis.
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Affiliation(s)
- Hisashi Hirano
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
| | - Hisamitsu Ide
- Department of Urology, Dokkyo Medical University Saitama Medical Center, Japan
| | - Yan Lu
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
| | - Yasuyuki Inoue
- Department of Urology, Dokkyo Medical University Saitama Medical Center, Japan
| | - Hiroshi Okada
- Department of Urology, Dokkyo Medical University Saitama Medical Center, Japan
| | - Shigeo Horie
- Department of Urology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
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Guo S, Ma B, Jiang X, Li X, Jia Y. Astragalus Polysaccharides Inhibits Tumorigenesis and Lipid Metabolism Through miR-138-5p/SIRT1/SREBP1 Pathway in Prostate Cancer. Front Pharmacol 2020; 11:598. [PMID: 32431616 PMCID: PMC7214922 DOI: 10.3389/fphar.2020.00598] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 04/17/2020] [Indexed: 12/31/2022] Open
Abstract
Astragalus polysaccharides (APS) is a traditional Chinese medicine and have been proved to involve in multiple biological processes, including inflammation, metabolism, and carcinogenics. However, the specific mechanisms by which APS on prostate cancer (PCa) remains largely unknown. In the current study, we found APS greatly inhibited the proliferation and invasion of PCa cells in a dose-dependent and time-dependent manner in vitro and in vivo. In addition, cellular triglyceride and cholesterol levels were also decreased significantly under APS treatment. Microarray data revealed the SIRT1 expression was markably suppressed under APS exposure. Mechanistic studies demonstrated that over-expression of SIRT1 inhibits the expression and nuclear translocation of SREBP1 via activating AMPK phosphorylation to suppress lipid metabolism. Otherwise, knockdown of SIRT1 significantly promotes AMPK/SREBP1 signaling and its associated target genes. Besides, we also found miR-138-5p was greatly inhibited the SIRT1 expression to regulating cell metabolism by targeting its 3′UTR region. To summarize, our findings suggested that APS inhibits tumorigenesis and lipid metabolism through miR-138-5p/SIRT1/SREBP1 pathways in PCa.
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Affiliation(s)
- Shanqi Guo
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Baojie Ma
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xingkang Jiang
- Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xiaojiang Li
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Dambal S, Alfaqih M, Sanders S, Maravilla E, Ramirez-Torres A, Galvan GC, Reis-Sobreiro M, Rotinen M, Driver LM, Behrove MS, Talisman TJ, Yoon J, You S, Turkson J, Chi JT, Freeman MR, Macias E, Freedland SJ. 27-Hydroxycholesterol Impairs Plasma Membrane Lipid Raft Signaling as Evidenced by Inhibition of IL6-JAK-STAT3 Signaling in Prostate Cancer Cells. Mol Cancer Res 2020; 18:671-684. [PMID: 32019810 DOI: 10.1158/1541-7786.mcr-19-0974] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/04/2020] [Accepted: 01/29/2020] [Indexed: 01/04/2023]
Abstract
We recently reported that restoring the CYP27A1-27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti-prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6-JAK-STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6-JAK-STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation. IMPLICATIONS: Collectively, these data show that modulation of intracellular cholesterol by 27HC can inhibit IL6-JAK-STAT signaling and may synergize with STAT3-targeted compounds.
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Affiliation(s)
- Shweta Dambal
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina
| | | | - Sergio Sanders
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Erick Maravilla
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina
| | - Adela Ramirez-Torres
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Gloria C Galvan
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mariana Reis-Sobreiro
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mirja Rotinen
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Lucy M Driver
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina
| | - Matthew S Behrove
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, California
| | - Tijana Jovanovic Talisman
- Department of Molecular Medicine, Beckman Research Institute of the City of Hope Comprehensive Cancer Center, Duarte, California
| | - Junhee Yoon
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Sungyong You
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - James Turkson
- Department of Biomedical Science, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jen-Tsan Chi
- Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina
| | - Michael R Freeman
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California.,Department of Biomedical Science, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Everardo Macias
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
| | - Stephen J Freedland
- Department of Surgery, Samuel Oschin Comprehensive Cancer Center, Cedars-Sinai Medical Center, Los Angeles, California. .,Section of Urology, Durham VA Medical Center, Durham, North Carolina
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Desikan SP, Sobash P, Fisher A, Desikan R. Statin-Induced Rhabdomyolysis Due to Pharmacokinetic Changes From Biliary Obstruction in a Patient With Metastatic Prostate Cancer. J Investig Med High Impact Case Rep 2020; 8:2324709620947275. [PMID: 32755252 PMCID: PMC7543161 DOI: 10.1177/2324709620947275] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Statins work synergistically with androgen receptor blockers and androgen biosynthesis inhibitors, improving survival in patients with metastatic castration resistant prostate cancers (mCRPCs). Survival improvement is more pronounced for patients receiving androgen biosynthesis inhibitors compared with patients receiving androgen receptor blockers. A rare adverse interaction between simvastatin and abiraterone (Zytiga), an androgen biosynthesis inhibitor, was observed in a patient with mCRPC due to pharmacokinetic changes resulting from obstructive jaundice.
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Gan S, Ye J, Li J, Hu C, Wang J, Xu D, Pan X, Chu C, Chu J, Zhang J, Zheng J, Zhang X, Xu J, Zhang H, Qu F, Cui X. LRP11 activates β-catenin to induce PD-L1 expression in prostate cancer. J Drug Target 2019; 28:508-515. [PMID: 31865764 DOI: 10.1080/1061186x.2019.1687710] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Prostate cancer (PRAD) is associated with abnormal cholesterol metabolism and low-density lipoprotein (LDL) receptor-related protein (LRP) family is essential for the homeostasis of cholesterol. Immune check points like PD-L1 are vital for tumour cells to evade immune attack. However, the potential cross-talk between these two pathways has not been explored before in PRAD. Insight from the regulation mechanism of PD-L1 in PRAD may help to optimise PD-L1 based immunotherapy. In this study, we investigated a regulation network of LRP11/β-catenin/PD-L1 in PRAD. We showed that the expression of LRP11 and PD-L1 was up-regulated in PRAD compared to paired normal tissues. LRP11 expression was positively correlated to PD-L1 expression in PRAD tissues. Further experiments in two PRAD cell lines with LRP11 over-expression and knockdown showed that LRP11 induced PD-L1 expression through β-catenin signalling. In addition, LRP11 over-expression in PRAD cell line induced immunosuppression of Jurkat cell in in-vitro co-culture system. The effects of LRP11 could be blocked by neutralising LRP11 or PD-L1 antibody. Our results provide evidence for a novel regulation mechanism of PD-L1 expression in PRAD and LRP11 may be a potential therapeutic target in PRAD.
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Affiliation(s)
- Sishun Gan
- Department of Urology, Third Affiliated Hospital of Second Military Medical University, Shanghai, PR China
| | - Jianqing Ye
- Department of Urology, Third Affiliated Hospital of Second Military Medical University, Shanghai, PR China
| | - Jian Li
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Chuanyi Hu
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Junkai Wang
- Department of Urology, Changzheng Hospital of Second Military Medical University, Shanghai, PR China
| | - Da Xu
- Department of Urology, Third Affiliated Hospital of Second Military Medical University, Shanghai, PR China
| | - Xiuwu Pan
- Department of Urology, Third Affiliated Hospital of Second Military Medical University, Shanghai, PR China
| | - Chuanmin Chu
- Department of Urology, Third Affiliated Hospital of Second Military Medical University, Shanghai, PR China
| | - Jian Chu
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Jing Zhang
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Jingcun Zheng
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Xiangmin Zhang
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Jidong Xu
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - He Zhang
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Fajun Qu
- Department of Urology, Gongli Hospital of the Second Military Medical University, Shanghai, PR China
| | - Xingang Cui
- Department of Urology, Third Affiliated Hospital of Second Military Medical University, Shanghai, PR China
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11
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Hirata Y, Shiota M, Kobayashi T, Kashiwagi E, Takeuchi A, Inokuchi J, Tatsugami K, Eto M. Prognostic significance of diabetes mellitus and dyslipidemia in men receiving androgen-deprivation therapy for metastatic prostate cancer. Prostate Int 2019; 7:166-170. [PMID: 31970142 PMCID: PMC6962726 DOI: 10.1016/j.prnil.2019.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 08/14/2019] [Accepted: 10/10/2019] [Indexed: 12/18/2022] Open
Abstract
Objective The outcome of the androgen-deprivation therapy (ADT) may be affected by metabolic diseases such as diabetes mellitus (DM) and dyslipidemia and/or by their treatments. We aimed to evaluate the prognostic impact of these disorders and corresponding medications in Japanese men treated with ADT for prostate cancer. Methods This study retrospectively included 121 patients with metastatic prostate cancer who were treated with primary ADT at our hospital between 2001 and 2013. All patients received primary ADT with castration and/or an antiandrogen agent (bicalutamide or flutamide). Associations between clinicopathological factors, metabolic disease profiles, medication use, and prognosis (progression-free survival [PFS] and overall survival [OS]) were evaluated by univariate and multivariate analysis. Results The median follow-up time was 54.9 months, and the median PFS and OS were 23.9 months and 73.0 months, respectively. High serum glucose levels at baseline (hazard ratio [HR], 95% confidence interval [CI]: 2.12, 1.16–3.76; P = 0.015), and concurrent DM (HR, 95% CI: 2.07, 1.06–3.94; P = 0.034) were significantly associated with poorer OS after adjustment for age, prostate-specific antigen levels at diagnosis, Gleason score, and clinical stage. Treatment with sulfonylurea drugs was significantly associated with a reduced risk of disease progression in men with DM (HR, 95% CI: 0.36, 0.12–0.90; P = 0.028). Conclusions Impaired glucose tolerance and treatment with sulfonylureas have prognostic significance in prostate cancer. These findings demonstrate the importance of managing DM during ADT and point to a possible favorable effect of sulfonylureas on prostate cancer.
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Affiliation(s)
- Yu Hirata
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Shiota
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Kobayashi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Kashiwagi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Ario Takeuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junichi Inokuchi
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsunori Tatsugami
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masatoshi Eto
- Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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12
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Nogueira-Lima E, Lamas CDA, Baseggio AM, do Vale JSF, Maróstica Junior MR, Cagnon VHA. High-fat diet effects on the prostatic adenocarcinoma model and jaboticaba peel extract intake: protective response in metabolic disorders and liver histopathology. Nutr Cancer 2019; 72:1366-1377. [DOI: 10.1080/01635581.2019.1684526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ellen Nogueira-Lima
- Department of Structural and Functional Biology, University of Campinas, São Paulo, Brazil
| | | | - Andressa Mara Baseggio
- Department of Structural and Functional Biology, University of Campinas, São Paulo, Brazil
- Department of Food and Nutrition, University of Campinas, São Paulo, Brazil
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13
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Zheng X, Han X, Xu H, Ai J, Yang L, Wei Q. Prognostic value of lipid profiles after radical prostatectomy: a systematic review and meta-analysis. Lipids Health Dis 2019; 18:124. [PMID: 31138210 PMCID: PMC6540553 DOI: 10.1186/s12944-019-1068-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 05/15/2019] [Indexed: 02/05/2023] Open
Abstract
Background Lipid profiles are believed to play an important role in the tumorigenesis and progression of prostate cancer (PCa), but research combining those data is lacking. Therefore, this meta-analysis aims to assess the prognostic role of lipid profiles after RP. Method We systematically searched PubMed, Embase, and Cochrane Library Central Register of Controlled Trials for articles evaluating association between lipid profiles and prognosis after RP. Odds ratio (OR) and hazard ratio (HR) of lipid profiles for advanced pathological tumor features and biochemical recurrence (BCR) were extracted and pooled OR and HR were calculated. Newcastle-Ottawa scale was used for study quality assessment and funnel plot was used for evaluating publication bias. Results Twelve articles involving 11,108 patients were eventually selected. We found low HDL was associated with more frequent occurrence of pathological T stage (pT) ≥ T3 (pooled OR = 1.29, 95% CI 1.07–1.56) and Gleason score (GS) ≥8 (pooled OR = 1.32, 95% CI 1.02–1.72) after RP. Hypertriglyceridemia was also linked with higher risk of pT ≥ T3 (pooled OR = 1.20, 95% CI 1.01–1.42) and positive surgical margin (PSM) (pooled OR = 1.36, 95% CI 1.11–1.65). However, no significant association was observed between BCR and abnormal lipid profile levels. Conclusion Low HDL level was associated with more common occurrence of pT ≥ T3 and GS ≥8, and elevated triglycerides level was linked higher risk of pT ≥ T3 and PSM, but none of the lipid subfractions was correlated with biochemical recurrence after RP. Electronic supplementary material The online version of this article (10.1186/s12944-019-1068-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaonan Zheng
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Xin Han
- West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Hang Xu
- West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jianzhong Ai
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Lu Yang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
| | - Qiang Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
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14
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Van Rompay MI, Solomon KR, Nickel JC, Ranganathan G, Kantoff PW, McKinlay JB. Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications. Eur J Cancer 2019; 112:118-126. [PMID: 30850323 PMCID: PMC6501826 DOI: 10.1016/j.ejca.2018.11.033] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/15/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Statins have demonstrated protection against aggressive/late-stage and/or lethal prostate cancer (PC), but prior studies are limited by small populations, short follow-up and unequal health-care access. Research has not demonstrated that non-statin lipid-lowering medications (NSLLMs) provide a similar benefit, which would support a cholesterol-based mechanism. We sought to rigorously test the hypothesis that cholesterol-lowering drugs affect PC incidence and severity. METHODS A retrospective cohort study was conducted by abstracting prescription and health service records for 249,986 Saskatchewan men aged ≥40 years between January 1, 1990 and December 31, 2014 and comparing first-time statin and NSLLM users with age-matched non-users and glaucoma medication (GM) users for PC incidence, metastases at diagnosis and PC mortality using Cox proportional hazards regression. RESULTS In comparing statin users to non-users, a weak association was detected with increased PC incidence (hazard ratio [HR] 1.07, 95% confidence interval [CI]: 1.02-1.12) that disappeared when compared with GM users. Substantial protective associations were observed between statin use and metastatic PC and PC mortality (HRs 0.69, 95% CI: 0.61-0.79 and 0.73, 95% CI: 0.66-0.81, respectively), which were stronger when compared with GM use (HRs 0.52, 95% CI: 0.40-0.68 and 0.51, 95% CI: 0.41-0.63, respectively). Similar associations were found for NSLLM versus GM for metastatic PC (HR 0.57, 95% CI: 0.41-0.79) and PC mortality (HR 0.66, 95% CI: 0.51-0.85). CONCLUSIONS Our analyses provide one of the more comprehensive findings to date that statins may reduce risk of metastatic PC and PC mortality, and the first to demonstrate that NSLLM have similar effects, supporting a cholesterol-based mechanism.
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Affiliation(s)
| | - Keith R Solomon
- Department of Orthopaedic Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA; Department of Urology, Boston Children's Hospital, Boston, MA 02115, USA.
| | - J Curtis Nickel
- Department of Urology, Queen's University, Kingston, ON, Canada.
| | | | - Philip W Kantoff
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - John B McKinlay
- HealthCore-NERI, 480 Pleasant Street, Watertown, MA 02472, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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15
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Di Francesco S, Robuffo I, Caruso M, Giambuzzi G, Ferri D, Militello A, Toniato E. Metabolic Alterations, Aggressive Hormone-Naïve Prostate Cancer and Cardiovascular Disease: A Complex Relationship. ACTA ACUST UNITED AC 2019; 55:medicina55030062. [PMID: 30866568 PMCID: PMC6473682 DOI: 10.3390/medicina55030062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/30/2019] [Accepted: 02/27/2019] [Indexed: 02/06/2023]
Abstract
Background: Epidemiological studies suggest a possible relationship between metabolic alterations, cardiovascular disease and aggressive prostate cancer, however, no clear consensus has been reached. Objective: The aim of the study was to analyze the recent literature and summarize our experience on the association between metabolic disorders, aggressive hormone-naïve prostate cancer and cardiovascular disease. Method: We identified relevant papers by searching in electronic databases such as Scopus, Life Science Journals, and Index Medicus/Medline. Moreover, we showed our experience on the reciprocal relationship between metabolic alterations and aggressive prostate cancer, without the influence of hormone therapy, as well the role of coronary and carotid vasculopathy in advanced prostate carcinoma. Results: Prostate cancer cells have an altered metabolic homeostatic control linked to an increased aggressivity and cancer mortality. The absence of discrimination of risk factors as obesity, systemic arterial hypertension, diabetes mellitus, dyslipidemia and inaccurate selection of vascular diseases as coronary and carotid damage at initial diagnosis of prostate cancer could explain the opposite results in the literature. Systemic inflammation and oxidative stress associated with metabolic alterations and cardiovascular disease can also contribute to prostate cancer progression and increased tumor aggressivity. Conclusions: Metabolic alterations and cardiovascular disease influence aggressive and metastatic prostate cancer. Therefore, a careful evaluation of obesity, diabetes mellitus, dyslipidemia, systemic arterial hypertension, together with a careful evaluation of cardiovascular status, in particular coronary and carotid vascular disease, should be carried out after an initial diagnosis of prostatic carcinoma.
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Affiliation(s)
- Simona Di Francesco
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
| | - Iole Robuffo
- Institute of Molecular Genetics, National Research Council, Section of Chieti, 66100 Chieti, Italy.
| | - Marika Caruso
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
| | - Giulia Giambuzzi
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
| | - Deborah Ferri
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
| | - Andrea Militello
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
- Urology and Andrology Section, Villa Immacolata Hospital, 01100 Viterbo, Italy.
| | - Elena Toniato
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
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16
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Sánchez Lasheras JE, Suárez Gómez SL, Santos JD, Castaño-Vinyals G, Pérez-Gómez B, Tardón A. A multivariate regression approach for identification of SNPs importance in prostate cancer. J EXP THEOR ARTIF IN 2018. [DOI: 10.1080/0952813x.2018.1552319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
| | | | | | - Gemma Castaño-Vinyals
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
- ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
| | - Beatriz Pérez-Gómez
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Cancer and Environmental Epidemiology Unit, Carlos III Institute of Health, National Center for Epidemiology, Madrid, Spain
| | - Adonina Tardón
- Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Universitary Institute of Oncology of Asturias (IUOPA), University of Oviedo, Oviedo, Spain
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17
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Statin use and time to progression in men on active surveillance for prostate cancer. Prostate Cancer Prostatic Dis 2018; 21:509-515. [DOI: 10.1038/s41391-018-0053-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 03/15/2018] [Accepted: 03/24/2018] [Indexed: 11/08/2022]
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18
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Caro-Maldonado A, Camacho L, Zabala-Letona A, Torrano V, Fernández-Ruiz S, Zamacola-Bascaran K, Arreal L, Valcárcel-Jiménez L, Martín-Martín N, Flores JM, Cortazar AR, Zúñiga-García P, Arruabarrena-Aristorena A, Guillaumond F, Cabrera D, Falcón-Perez JM, Aransay AM, Gomez-Muñoz A, Olivan M, Morote J, Carracedo A. Low-dose statin treatment increases prostate cancer aggressiveness. Oncotarget 2017; 9:1494-1504. [PMID: 29416709 PMCID: PMC5788577 DOI: 10.18632/oncotarget.22217] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 10/13/2017] [Indexed: 11/25/2022] Open
Abstract
Prostate cancer is diagnosed late in life, when co-morbidities are frequent. Among them, hypertension, hypercholesterolemia, diabetes or metabolic syndrome exhibit an elevated incidence. In turn, prostate cancer patients frequently undergo chronic pharmacological treatments that could alter disease initiation, progression and therapy response. Here we show that treatment with anti-cholesterolemic drugs, statins, at doses achieved in patients, enhance the pro-tumorigenic activity of obesogenic diets. In addition, the use of a mouse model of prostate cancer and human prostate cancer xenografts revealed that in vivo simvastatin administration alone increases prostate cancer aggressiveness. In vitro cell line systems supported the notion that this phenomenon occurs, at least in part, through the direct action on cancer cells of low doses of statins, in range of what is observed in human plasma. In sum, our results reveal a prostate cancer experimental system where statins exhibit an undesirable effect, and warrant further research to address the relevance and implications of this observation in human prostate cancer.
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Affiliation(s)
| | - Laura Camacho
- CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.,Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain
| | | | - Verónica Torrano
- CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.,CIBERONC, Madrid, Spain
| | | | | | - Leire Arreal
- CIC bioGUNE, Bizkaia Technology Park, Derio, Spain
| | | | | | - Juana M Flores
- Department of Animal Medicine and Surgery, School of Veterinary Medicine, Complutense University of Madrid, Madrid, Spain
| | | | | | | | - Fabienne Guillaumond
- Centre de Recherche en Cancérologie de Marseille, U1068, Institut National de la Santé et de la Recherche Médicale, Paris, France.,Institut Paoli-Calmettes, Marseille, France.,UMR 7258, Centre National de la Recherche Scientifique, Paris, France.,Université Aix-Marseille, Marseille, France
| | | | - Juan M Falcón-Perez
- CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.,IKERBASQUE, Basque foundation for science, Bilbao, Spain
| | - Ana M Aransay
- CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Antonio Gomez-Muñoz
- Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain
| | - Mireia Olivan
- Department of Urology and Research Group in Urology, Vall d´Hebron Hospital, Vall d´Hebron Research Institute, and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Juan Morote
- Department of Urology and Research Group in Urology, Vall d´Hebron Hospital, Vall d´Hebron Research Institute, and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Arkaitz Carracedo
- CIC bioGUNE, Bizkaia Technology Park, Derio, Spain.,Biochemistry and Molecular Biology Department, University of the Basque Country, Bilbao, Spain.,CIBERONC, Madrid, Spain.,IKERBASQUE, Basque foundation for science, Bilbao, Spain
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19
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Clinical significance of pre-surgical serum lipid levels in patients with glioblastoma. Oncotarget 2017; 8:85940-85948. [PMID: 29156768 PMCID: PMC5689658 DOI: 10.18632/oncotarget.20730] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 07/30/2017] [Indexed: 02/05/2023] Open
Abstract
Accumulating evidence demonstrates that pre-surgical serum lipid levels are linked to the clinical outcome of different types of human malignant tumors, but few studies have explored the prognostic value of these easily accessible parameters in glioblastoma. The aim of the current study was to validate the association between pre-surgical serum lipid levels and the clinical outcome of patients with glioblastoma. The pre-surgical serum lipid levels (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, and low-density lipoprotein [LDL] cholesterol) of 125 patients with glioblastoma, who underwent surgery between January 2015 and May 2016, were retrospectively evaluated. The correlation between pre-surgical serum lipid levels and overall survival (OS) was examined using the Kaplan-Meier method and Cox proportional hazards regression model. Univariate analysis showed that lipids associated with OS were total cholesterol, HDL cholesterol, and LDL cholesterol levels. Results of multivariate analysis identified LDL cholesterol level as an independent prognostic factor for OS in patients with glioblastoma (hazard ratio: 0.412; 95% confidence interval: 0.211-0.801; P = 0.009). Total cholesterol and HDL cholesterol levels were predictive factors only in univariate analysis, but not in multivariate analysis. The current study demonstrated that pre-surgical serum LDL cholesterol level is an independent prognostic factor for clinical outcomes of patients with glioblastoma. Pre-surgical serum LDL cholesterol level might provide valuable prognostic information for patients with glioblastoma that could be applied in clinical practice.
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