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Hu Q, Wang M, Chen M, Wang J, Niu T. Toosendanin Induces Cell Cycle Arrest and Apoptosis to Suppress Diffuse Large B-Cell Lymphoma Growth by Inhibiting PI3Kα/β and PLK1 Signaling. Phytother Res 2025; 39:1930-1945. [PMID: 39949030 DOI: 10.1002/ptr.8439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 12/17/2024] [Accepted: 01/05/2025] [Indexed: 03/17/2025]
Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous subtype of non-Hodgkin lymphoma, with two-thirds of patients relapsing or resisting existing therapies, highlighting the urgent need for effective treatments. Toosendanin (TSN), a triterpenoid from Meliae Cortex, exhibits significant anti-cancer activity by modulating cell survival and proliferation. This study investigates the anti-lymphoma effects and underlying mechanisms of TSN, proposing it as a potential therapeutic agent to address the challenges of DLBCL. Network pharmacology, molecular docking, and transcriptome sequencing were employed to predict TSN's anti-DLBCL potential. Findings were validated through in vitro and in vivo experiments, including cell viability assays, flow cytometry, quantitative PCR, Western blotting, reverse experiments with small-molecule inhibitors or genetic editing, and a cell-derived xenograft (CDX) model. Bioinformatics analyses revealed TSN's strong binding affinity to PI3Kα/β and Polo-like kinase 1 (PLK1). Experiments showed that TSN downregulated the PI3K/Akt signaling pathway and reduced PLK1 mRNA and protein levels, inducing apoptosis, cell cycle arrest, and cell death in DLBCL cells. RNA sequencing and metabolic assays indicated TSN upregulated cholesterol biosynthesis in DLBCL cells. Co-treatment with a statin enhanced TSN's anti-DLBCL effects while mitigating hepatic and pulmonary toxicity. This study identifies TSN as a dual inhibitor of PI3K and PLK1 with significant therapeutic potential for DLBCL. It also proposes a lipid-modulating strategy to enhance TSN's cytotoxicity while reducing adverse effects, offering a promising approach to improve DLBCL treatment outcomes.
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Affiliation(s)
- Qian Hu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China
| | - Mengyao Wang
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China
| | - Meng Chen
- West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China
| | - Jinjin Wang
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China
| | - Ting Niu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- National Facility for Translational Medicine (Sichuan), West China Hospital, Sichuan University, Chengdu, China
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Hsieh MJ, Chen DY, Lee CH, Liao YC, Lin MS, Pang JHS. Canagliflozin-driven cellular re-differentiation and migration inhibition in vascular smooth muscle cells via PTEN upregulation. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04179-8. [PMID: 40304747 DOI: 10.1007/s00210-025-04179-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 04/11/2025] [Indexed: 05/02/2025]
Abstract
The phenotypic modulation of vascular smooth muscle cells (VSMCs) is a key factor in the development and progression of atherosclerosis. Canagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown efficacy in reducing atherosclerotic lesions; however, its specific effects on VSMC phenotype expression and the underlying intracellular signaling remain poorly understood. This study utilized VSMCs from rat aortic explants to evaluate the impact of canagliflozin on cell outgrowth, migration, cellular morphology, expression of phenotypic markers, and intracellular signaling. Canagliflozin significantly inhibited VSMC outgrowth and migration in a dose-dependent manner. Additionally, it induced an elongated VSMC morphology consistent with a contractile phenotype, while increasing the expression of contractile markers such as myocardin and calponin and reducing the expression of synthetic markers, including collagen I and III. Western blot study revealed that canagliflozin upregulated PTEN expression and suppressed AKT activation, both critical regulators of VSMC phenotype. Notably, PTEN knockdown via RNA interference reversed the inhibitory effects of canagliflozin on VSMC migration and phenotype switching, underscoring the central role of PTEN in these processes. These findings suggest that canagliflozin promotes a contractile phenotype in VSMCs by modulating the expression of phenotypic markers, upregulating PTEN, and downregulating AKT activation, thereby potentially inhibiting VSMC migration.
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Affiliation(s)
- Ming-Jer Hsieh
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan, ROC
- School of Medicine, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC
| | - Dong-Yi Chen
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan, ROC
| | - Cheng-Hung Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, No. 5, Fuxing St., Guishan Dist., Taoyuan City, 33305, Taiwan, ROC
- School of Medicine, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC
| | - Yu-Cih Liao
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC
| | - Miao-Sui Lin
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC
| | - Jong-Hwei S Pang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, No. 259, Wenhua 1 st Rd., Guishan Dist., Taoyuan City, 33302, Taiwan, ROC.
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Soni S, Makwana SH, Bansal S, Kumari M, Mandal CC. Lipid metabolism associated PLPP4 gene drives oncogenic and adipogenic potential in breast cancer cells. Biochim Biophys Acta Mol Cell Biol Lipids 2025; 1870:159609. [PMID: 40187483 DOI: 10.1016/j.bbalip.2025.159609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 03/16/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Lipid metabolic reprogramming plays a pivotal role in cancer cell evolution and causing subsequent cancer growth, metastasis and therapy resistance. Cancer associated adipocyte and/or cancer derived adipocyte-like cells often supply fuels and various factors to fulfill the cells bioenergetics to enhance oncogenic potential. This study intends to find out a set of dysregulated genes involved in lipid metabolism in breast cancer studies and uncovers the role of unexplored dysregulated gene in cancer potential. Cancer database analysis determines seven seed signature genes (PLPP2, PLPP4, CDS1, ASAH2, LCLAT1, LPCAT1 and LASS6/CERS6) concluded from relative expression and survival analysis. Furthermore, experimental analysis unveils the gene PLPP4 (Phospholipid Phosphatase 4) as oncogene confirmed by knockdown and overexpression studies in MDA-MB 231 and MCF-7 breast cancer cells. PLPP4 enzyme is involved in regulation of triacyl glycerol metabolism. Lipid accumulation along with other studies documented enhanced lipid droplets, TAG formation and glycerol release with concomitant increased expressions of various adipogenic markers (e.g., PPARγ, perilipin 1 and leptin) in breast cancer cells transfected with PLPP4 gene expressing plasmid whereas downregulation of PLPP4 gene diminished lipid accumulation and adipocyte marker gene expressions. Our findings also revealed that BMP2 induced adipogenic potential in breast cancer cells was mitigated in response to downregulation of PLPP4 gene expression. All these findings together, for first time, demonstrated that BMP2 drives PLPP4 to enhance both oncogenic and adipogenic potential in breast cancer cells. This article uncovers the perturbed lipid metabolism associated PLPP4 acts as oncogene presumably by modulating adipogenic activity in cancer cells.
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Affiliation(s)
- Sneha Soni
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan 305817, India
| | - Sweta H Makwana
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan 305817, India
| | - Shivani Bansal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan 305817, India
| | - Monika Kumari
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan 305817, India
| | - Chandi C Mandal
- Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan 305817, India.
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Guo XJ, Zhu BB, Li J, Guo P, Niu YB, Shi JL, Yokoyama W, Huang QS, Shao DY. Cholesterol metabolism in tumor immunity: Mechanisms and therapeutic opportunities for cancer. Biochem Pharmacol 2025; 234:116802. [PMID: 39954742 DOI: 10.1016/j.bcp.2025.116802] [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: 10/31/2024] [Revised: 12/25/2024] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Cholesterol is an essential component of the cell membrane which plays a critical role in the survival of immune and tumor cells. Reprogramming of cholesterol metabolism in both tumor cells and immune cells can impact tumor progression and anti-tumor immune responses. Strategies aimed at modulating cholesterol metabolism have been demonstrated to be effective in hindering tumor growth and boosting anti-tumor immune functions. This review provides a thorough analysis of intracellular cholesterol homeostasis regulation in cells, focusing on key genes and signaling pathways. It particularly emphasizes the regulatory mechanisms and importance of the cholesterol presence state (esterified/free), levels of cholesterol, and its metabolites in immune and tumor cells. Additionally, the review thoroughly explores how cholesterol metabolism and sources (endogenous/exogenous) in the tumor microenvironment (TME) contribute to the interplay among tumor cells, immune suppressor cells, and immune effector cells, promoting cancer progression and immune evasion. It also delves into current insights on the influence of cholesterol metabolites and related drugs in regulating tumor development or immunotherapy. Finally, it presents an overview of recent advancements in clinical and preclinical trials investigating the efficacy of targeted cholesterol metabolism treatments and combination therapies in cancer management, while proposing potential future research directions in tumor immunity. This review is poised to offer fresh perspectives and avenues for examining the potential of cancer immunotherapy centered on cholesterol metabolism regulation.
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Affiliation(s)
- Xiao-Jia Guo
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China
| | - Bo-Bo Zhu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China
| | - Jing Li
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710072, PR China
| | - Ping Guo
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China
| | - Yin-Bo Niu
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China
| | - Jun-Ling Shi
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China
| | - Wallace Yokoyama
- Processed Foods Research Unit, Western Regional Research Center, Agricultural Research Service, USDA, Albany, CA 94710, USA
| | - Qing-Sheng Huang
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China.
| | - Dong-Yan Shao
- Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, 127 Youyi West Road, Xi'an, Shaanxi 710072, PR China; Research & Development Institute of Northwestern Polytechnical University in Shenzhen, No. 45th, Gaoxin South 9th Road, Nanshan District, Shenzhen City 518063, PR China.
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Codenotti S, Asperti M, Poli M, Lorenzi L, Pietrantoni A, Cassandri M, Marampon F, Fanzani A. Synthetic inhibition of SREBP2 and the mevalonate pathway blocks rhabdomyosarcoma tumor growth in vitro and in vivo and promotes chemosensitization. Mol Metab 2025; 92:102085. [PMID: 39706565 PMCID: PMC11750561 DOI: 10.1016/j.molmet.2024.102085] [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: 09/26/2024] [Revised: 12/03/2024] [Accepted: 12/12/2024] [Indexed: 12/23/2024] Open
Abstract
OBJECTIVE The aim of the present study was to investigate the effects of targeting the mevalonate pathway (MVP) in rhabdomyosarcoma (RMS), a soft tissue tumor with a prevalence in young people. METHODS In silico analyses of RNA datasets were performed to correlate MVP with RMS patient survival. The sensitivity of RMS cell lines to MVP inhibitors was assessed in vitro by analysis of cell growth (crystal violet and clonogenic assays), cell migration (wound healing assay), cell survival (neutral red assay), and oxidative stress (ROS assay). The effects of MVP inhibitors were tested in vivo by analyzing RMS xenografts grown in NOD/SCID mice. Quantification of protein targets was performed using immunoblotting or immunohistochemistry analyses. RESULTS In silico analysis showed upregulation of sterol regulatory element-binding protein 2 (SREBP2) and MVP genes, including 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), farnesyl-diphosphate synthase (FDPS), squalene epoxidase (SQLE), which correlated with worse overall patient survival. Targeting of MVP in human RD and RH30 lines by inhibitors of SREBP2 (fatostatin), HMGCR (lovastatin and simvastatin), and FDPS (zoledronic acid) resulted in impaired cell growth, migration, and viability, and increased oxidative cell death in combination with actinomycin D. Conversely, cholesterol (CHO) supplementation enhanced cell growth and migration. Fatostatin and lovastatin produced rapid attenuation of Erk1/2 and Akt1 signaling in RMS lines, and oral administration of lovastatin reduced tumor mass growth of xenografted RD cells in NOD/SCID mice. Finally, we found that forced Akt1 activation in RD cells was sufficient to drive SREBP2, HMGCR and SQLE protein expression, promoting increased susceptibility to MVP inhibitors. CONCLUSIONS These data suggest that the Akt1, SREBP2 and MVP axis is critical for RMS tumor growth, migration, and oxidative stress protection primarily through maintaining adequate CHO levels that enable proper intracellular signaling. Therefore, stimulating CHO depletion via SREBP2 and MVP inhibition may represent a viable option to improve the combination therapy protocol, especially in pAkt1-positive RMS.
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Affiliation(s)
- Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
| | - Michela Asperti
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Luisa Lorenzi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; ASST Spedali Civili di Brescia, 25123, Brescia, Italy
| | - Alberto Pietrantoni
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; ASST Spedali Civili di Brescia, 25123, Brescia, Italy
| | - Matteo Cassandri
- Department of Radiological Sciences, Oncology and Anatomic Pathology, "Sapienza" University of Rome, 00161, Rome, Italy
| | | | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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Lagunas-Rangel FA, Liepinsh E, Fredriksson R, Alsehli AM, Williams MJ, Dambrova M, Jönsson J, Schiöth HB. Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases. Br J Pharmacol 2024; 181:3799-3818. [PMID: 39180421 DOI: 10.1111/bph.17309] [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: 04/23/2024] [Revised: 06/25/2024] [Accepted: 07/10/2024] [Indexed: 08/26/2024] Open
Abstract
Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.
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Affiliation(s)
- Francisco Alejandro Lagunas-Rangel
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
| | - Edgars Liepinsh
- Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
| | - Robert Fredriksson
- Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
| | - Ahmed M Alsehli
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | - Michael J Williams
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Maija Dambrova
- Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
- Department of Pharmaceutical Chemistry, Riga Stradiņš University, Riga, Latvia
| | - Jörgen Jönsson
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
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Diallo A, Abbas M, Goodney G, Price E, Gaye A. Relationship between LDL-cholesterol, small and dense LDL particles, and mRNA expression in a cohort of African Americans. Am J Physiol Heart Circ Physiol 2024; 327:H690-H700. [PMID: 39028281 PMCID: PMC11901346 DOI: 10.1152/ajpheart.00332.2024] [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: 05/21/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/20/2024]
Abstract
Understanding the characteristics and behavior of low-density lipoprotein (LDL) particles provides insights into the atherogenic risk of elevated LDL cholesterol in hypercholesterolemia, cardiovascular disease risks. Studying LDL particles helps identify specific LDL subtypes [e.g., small dense LDL particles (sdLDL)] that may be atherogenic and, consequently, potential targets for therapeutics. This study cohort consists of African Americans (AAs), a population disproportionately affected by cardiovascular diseases, thereby accentuating the importance of the investigation. Differential expression (DE) analysis was undertaken using a dataset comprising 17,947 protein-coding mRNAs from the whole blood transcriptomes of 416 samples to identify mRNAs associated with low-density lipoprotein cholesterol (LDL-C) and sdLDL plasma levels. Subsequently, mediation analyses were used to investigate the mediating role of sdLDL particles on the relationship between LDL-C levels and mRNA expression. Finally, pathway enrichment analysis was conducted to identify pathways involving mRNAs whose relationship with LDL-C is mediated by sdLDL. DE analysis revealed 1,048 and 284 mRNA transcripts differentially expressed by LDL-C and sdLDL levels, respectively. Mediation analysis revealed that the associations between LDL-C and 33 mRNAs were mediated by sdLDL. Of the 33 mRNAs mediated by sdLDL, 18 were mediated in both males and females. Nine mRNAs were mediated only in females, and six were mediated only in males. Pathway analysis showed that 33 mRNAs are involved in pathways associated with the immune system, inflammatory response, metabolism, and cardiovascular disease (CVD) risk. In conclusion, our study provides valuable insights into the complex interplay between LDL-C, sdLDL, and mRNA expression in a large sample of AAs. The results underscore the importance of incorporating sdLDL measurement alongside LDL-C levels to improve the accuracy of managing hypercholesterolemia and effectively stratify the risk of CVD. This is essential as differences in sdLDL modulate atherogenic properties at the transcriptome level.NEW & NOTEWORTHY The study investigated the interplay between LDL-C and mRNA expression, focusing on the role of small dense LDL (sdLDL) particles and sex differences. Differential expression analysis identified 1,048 and 284 mRNAs associated with LDL-C and sdLDL levels, respectively. Mediation analysis revealed that sdLDL mediates the relationship between LDL-C and 33 mRNAs involved in immune, inflammatory, and metabolic pathways. These findings highlight the significance of sdLDL in cardiovascular disease risk assessment and underscore sex-specific differences in lipid metabolism.
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Affiliation(s)
- Ana Diallo
- School of Nursing, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Malak Abbas
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Gabriel Goodney
- National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States
| | - Elvin Price
- Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Amadou Gaye
- Department of Integrative Genomics and Epidemiology, School of Graduate Studies, Meharry Medical College, Nashville, Tennessee, United States
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Hosseini FS, Ahmadi A, Kesharwani P, Hosseini H, Sahebkar A. Regulatory effects of statins on Akt signaling for prevention of cancers. Cell Signal 2024; 120:111213. [PMID: 38729324 DOI: 10.1016/j.cellsig.2024.111213] [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: 03/11/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024]
Abstract
Statins, which are primarily used as lipid-lowering drugs, have been found to exhibit anti-tumor effects through modulating and interfering with various signaling pathways. In observational studies, statin use has been associated with a significant reduction in the progression of various cancers, including colon, lung, prostate, pancreas, and esophagus cancer, as well as melanoma and B and T cell lymphoma. The mevalonate pathway, which is affected by statins, plays a crucial role in activating Rho, Ras, and Rab proteins, thereby impacting the proliferation and apoptosis of tumor cells. Statins block this pathway, leading to the inhibition of isoprenoid units, which are critical for the activation of these key proteins, thereby affecting cancer cell behavior. Additionally, statins affect MAPK and Cdk2, which in turn reduce the expression of p21 and p27 cyclin-dependent kinase inhibitors. Akt signaling plays a crucial role in key cancer cell features like proliferation, invasion, and apoptosis by activating multiple effectors in downstream pathways such as FOXO, PTEN, NF-κB, GSK3β, and mTOR. The PI3K/Akt signaling is necessary for many events in the metastatic pathway and has been implicated in the resistance to cytostatic drugs. The Akt/PTEN axis is currently attracting great interest for its role in carcinogenesis. Statins have been shown to activate the purinergic receptor P2X7 and affect Akt signaling, which may have important anti-cancer effects. Hence, targeting Akt shows promise as an effective approach to cancer prevention and therapy. This review aims to provide a comprehensive discussion on the specific impact of statins through Akt signaling in different types of cancer.
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Affiliation(s)
- Fatemeh Sadat Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdolreza Ahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Butt E, Günder T, Stürzebecher P, Kowalski I, Schneider P, Buschmann N, Schäfer S, Bender A, Hermanns HM, Zernecke A. Cholesterol uptake in the intestine is regulated by the LASP1-AKT-NPC1L1 signaling pathway. Am J Physiol Gastrointest Liver Physiol 2024; 327:G25-G35. [PMID: 38713618 DOI: 10.1152/ajpgi.00222.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 04/16/2024] [Accepted: 04/26/2024] [Indexed: 05/09/2024]
Abstract
Cholesterol is essential for the stability and architecture of the plasma membrane and a precursor of bile acids and steroid hormones in mammals. Excess dietary cholesterol uptake leads to hypercholesterolemia and atherosclerosis and plays a role in cancer development. The role of actin-binding scaffolding protein LIM and SH3 protein 1 (LASP1) in cholesterol trafficking has not been investigated previously. Cholesterol levels, its uptake, and excretion were studied in mice deficient for low-density lipoprotein receptor and Lasp1 (Ldlr-/-Lasp1-/- mice) upon feeding a high-fat diet, and in LASP1-knockdown, differentiated human intestinal epithelial CaCo-2 cells. When compared with diet-fed Ldlr-/- control mice, Ldlr-/-Lasp1-/- mice displayed a reduction in serum cholesterol levels. Mechanistically, we identified a new role of LASP1 in controlling the translocation of the intestinal cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) to the apical cell surface, which was limited in LASP1-knockdown human CaCo-2 enterocytes and in the intestine of Ldlr-/- Lasp1-/- compared with Ldlr-/- mice, linked to LASP1-pAKT signaling but not CDC42 activation. In line, a reduction in cholesterol reabsorption was noted in LASP1-knockdown CaCo-2 cells in vitro, and an enhanced cholesterol excretion via the feces was observed in Ldlr-/- Lasp1-/- mice. These data uncover a novel function of Lasp1 in cholesterol trafficking, promoting cholesterol reabsorption in the intestine. Targeting LASP1 locally could thus represent a novel targeting strategy to ameliorate hypercholesterolemia and associated diseases.NEW & NOTEWORTHY We here uncovered LASP1 as a novel regulator of the shuttling of the sterol transporter NPC1L1 to the cell surface in enterocytes to control cholesterol absorption. Accordingly, LASP1-deficient mice displayed lowered serum cholesterol levels under dietary cholesterol supplementation.
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Affiliation(s)
- Elke Butt
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Thorsten Günder
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Paulina Stürzebecher
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Isabel Kowalski
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Pia Schneider
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Nils Buschmann
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Sarah Schäfer
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Alicia Bender
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Heike M Hermanns
- Division of Hepatology, University Hospital Würzburg, Würzburg, Germany
| | - Alma Zernecke
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
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10
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Tripathi S, Gupta E, Galande S. Statins as anti-tumor agents: A paradigm for repurposed drugs. Cancer Rep (Hoboken) 2024; 7:e2078. [PMID: 38711272 PMCID: PMC11074523 DOI: 10.1002/cnr2.2078] [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: 11/14/2023] [Revised: 03/28/2024] [Accepted: 04/15/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Statins, frequently prescribed medications, work by inhibiting the rate-limiting enzyme HMG-CoA reductase (HMGCR) in the mevalonate pathway to reduce cholesterol levels. Due to their multifaceted benefits, statins are being adapted for use as cost-efficient, safe and effective anti-cancer treatments. Several studies have shown that specific types of cancer are responsive to statin medications since they rely on the mevalonate pathway for their growth and survival. RECENT FINDINGS Statin are a class of drugs known for their potent inhibition of cholesterol production and are typically prescribed to treat high cholesterol levels. Nevertheless, there is growing interest in repurposing statins for the treatment of malignant neoplastic diseases, often in conjunction with chemotherapy and radiotherapy. The mechanism behind statin treatment includes targeting apoptosis through the BCL2 signaling pathway, regulating the cell cycle via the p53-YAP axis, and imparting epigenetic modulations by altering methylation patterns on CpG islands and histone acetylation by downregulating DNMTs and HDACs respectively. Notably, some studies have suggested a potential chemo-preventive effect, as decreased occurrence of tumor relapse and enhanced survival rate were reported in patients undergoing long-term statin therapy. However, the definitive endorsement of statin usage in cancer therapy hinges on population based clinical studies with larger patient cohorts and extended follow-up periods. CONCLUSIONS The potential of anti-cancer properties of statins seems to reach beyond their influence on cholesterol production. Further investigations are necessary to uncover their effects on cancer promoting signaling pathways. Given their distinct attributes, statins might emerge as promising contenders in the fight against tumorigenesis, as they appear to enhance the efficacy and address the limitations of conventional cancer treatments.
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Affiliation(s)
- Sneha Tripathi
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
| | - Ekta Gupta
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
| | - Sanjeev Galande
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
- Centre of Excellence in Epigenetics, Department of Life SciencesShiv Nadar Institution of EminenceGautam Buddha NagarIndia
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11
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Codenotti S, Sandrini L, Mandracchia D, Lorenzi L, Corsetti G, Poli M, Asperti M, Salvi V, Bosisio D, Monti E, Mitola S, Triggiani L, Guescini M, Pozzo E, Sampaolesi M, Gastaldello S, Cassandri M, Marampon F, Fanzani A. Statin-Sensitive Akt1/Src/Caveolin-1 Signaling Enhances Oxidative Stress Resistance in Rhabdomyosarcoma. Cancers (Basel) 2024; 16:853. [PMID: 38473215 PMCID: PMC11154391 DOI: 10.3390/cancers16050853] [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: 11/21/2023] [Revised: 02/07/2024] [Accepted: 02/14/2024] [Indexed: 03/14/2024] Open
Abstract
Identifying the molecular mechanisms underlying radioresistance is a priority for the treatment of RMS, a myogenic tumor accounting for approximately 50% of all pediatric soft tissue sarcomas. We found that irradiation (IR) transiently increased phosphorylation of Akt1, Src, and Cav1 in human RD and RH30 lines. Synthetic inhibition of Akt1 and Src phosphorylation increased ROS levels in all RMS lines, promoting cellular radiosensitization. Accordingly, the elevated activation of the Akt1/Src/Cav1 pathway, as detected in two RD lines characterized by overexpression of a myristoylated Akt1 form (myrAkt1) or Cav1 (RDCav1), was correlated with reduced levels of ROS, higher expression of catalase, and increased radioresistance. We found that treatment with cholesterol-lowering drugs such as lovastatin and simvastatin promoted cell apoptosis in all RMS lines by reducing Akt1 and Cav1 levels and increasing intracellular ROS levels. Combining statins with IR significantly increased DNA damage and cell apoptosis as assessed by γ histone 2AX (γH2AX) staining and FACS analysis. Furthermore, in combination with the chemotherapeutic agent actinomycin D, statins were effective in reducing cell survival through increased apoptosis. Taken together, our findings suggest that the molecularly linked signature formed by Akt1, Src, Cav1, and catalase may represent a prognostic determinant for identifying subgroups of RMS patients with higher probability of recurrence after radiotherapy. Furthermore, statin-induced oxidative stress could represent a treatment option to improve the success of radiotherapy.
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Affiliation(s)
- Silvia Codenotti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Leonardo Sandrini
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Delia Mandracchia
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Luisa Lorenzi
- Department of Molecular and Translational Medicine, University of Brescia, and ASST Spedali Civili di Brescia, 25123 Brescia, Italy;
| | - Giovanni Corsetti
- Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy;
| | - Maura Poli
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Michela Asperti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Daniela Bosisio
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Eugenio Monti
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Stefania Mitola
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
| | - Luca Triggiani
- Department of Radiation Oncology, ASST Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy;
| | - Michele Guescini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy;
| | - Enrico Pozzo
- Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (E.P.); (M.S.)
| | - Maurilio Sampaolesi
- Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium; (E.P.); (M.S.)
| | - Stefano Gastaldello
- Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden;
| | - Matteo Cassandri
- Department of Radiological Sciences, Oncology and Anatomic Pathology, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (F.M.)
| | - Francesco Marampon
- Department of Radiological Sciences, Oncology and Anatomic Pathology, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (F.M.)
| | - Alessandro Fanzani
- Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (L.S.); (D.M.); (M.P.); (M.A.); (V.S.); (D.B.); (E.M.); (S.M.)
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12
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Kwon J, Kim MS, Blagojevic C, Mailloux J, Medwid S, Tirona RG, Wang R, Schwarz UI. Differential effects of OATP2B1 on statin accumulation and toxicity in a beta cell model. Toxicol Mech Methods 2024; 34:130-147. [PMID: 37771097 DOI: 10.1080/15376516.2023.2262568] [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: 08/18/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023]
Abstract
An increased risk of new-onset diabetes mellitus has been recently reported for statin therapy, and experimental studies have shown reduced glucose-stimulated insulin secretion (GSIS) and mitochondrial dysfunction in beta cells with effects differing among agents. Organic anion transporting polypeptide (OATP) 2B1 contributes to hepatic uptake of rosuvastatin, atorvastatin and pravastatin, three known substrates. Since OATP2B1 is present in beta cells of the human pancreas, we investigated if OATP2B1 facilitates the local accumulation of statins in a rat beta cell model INS-1 832/13 (INS-1) thereby amplifying statin-induced toxicity. OATP2B1 overexpression in INS-1 cells via adenoviral transduction showed 2.5-, 1.8- and 1.4-fold higher cellular retention of rosuvastatin, atorvastatin and pravastatin, respectively, relative to LacZ control, while absolute intracellular concentration was about twice as high for the lipophilic atorvastatin compared to the more hydrophilic rosuvastatin and pravastatin. After 24 h statin treatment at high concentrations, OATP2B1 enhanced statin toxicity involving activation of intrinsic apoptosis (caspase 3/7 activation) and mitochondrial dysfunction (NADH dehydrogenase activity) following rosuvastatin and atorvastatin, which was partly reversed by isoprenoids. OATP2B1 had no effect on statin-induced reduction in GSIS, mitochondrial electron transport chain complex expression or caspase 9 activation. We confirmed a dose-dependent reduction in insulin secretion by rosuvastatin and atorvastatin in native INS-1 with a modest change in cellular ATP. Collectively, our results indicate a role of OATP2B1, which is abundant in human beta cells, in statin accumulation and statin-induced toxicity but not insulin secretion of rosuvastatin and atorvastatin in INS-1 cells.
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Affiliation(s)
- Jihoon Kwon
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Michelle S Kim
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Christina Blagojevic
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Jaymie Mailloux
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Samantha Medwid
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Rommel G Tirona
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Rennian Wang
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Ute I Schwarz
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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13
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Gyoten M, Luo Y, Fujiwara-Tani R, Mori S, Ogata R, Kishi S, Kuniyasu H. Lovastatin Treatment Inducing Apoptosis in Human Pancreatic Cancer Cells by Inhibiting Cholesterol Rafts in Plasma Membrane and Mitochondria. Int J Mol Sci 2023; 24:16814. [PMID: 38069135 PMCID: PMC10706654 DOI: 10.3390/ijms242316814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 11/24/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Resistance to anticancer drugs is a problem in the treatment of pancreatic ductal carcinoma (PDAC) and overcoming it is an important issue. Recently, it has been reported that statins induce apoptosis in cancer cells but the mechanism has not been completely elucidated. We investigated the antitumor mechanisms of statins against PDAC and their impact on resistance to gemcitabine (GEM). Lovastatin (LOVA) increased mitochondrial oxidative stress in PDAC cells, leading to apoptosis. LOVA reduced lipid rafts in the plasma membrane and mitochondria, suppressed the activation of epithelial growth factor receptor (EGFR) and AKT in plasma membrane rafts, and reduced B-cell lymphoma 2 (BCL2)-Bcl-2-associated X protein (BAX) binding and the translocation of F1F0 ATPase in mitochondrial rafts. In the three GEM-resistant cell lines derived from MIA and PANC1, the lipid rafts in the cell membrane and the mitochondria were increased to activate EGFR and AKT and to increase BCL2-BAX binding, which suppressed apoptosis. LOVA abrogated these anti-apoptotic effects by reducing the rafts in the resistant cells. By treating the resistant cells with LOVA, GEM sensitivity improved to the level of the parental cells. Therefore, cholesterol rafts contribute to drug resistance in PDAC. Further clinical research is warranted on overcoming anticancer drug resistance by statin-mediated intracellular cholesterol regulation.
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Grants
- 19K16564 Ministry of Education, Culture, Sports, Science and Technology
- 20K21659 Ministry of Education, Culture, Sports, Science and Technology
- 23K16621 Ministry of Education, Culture, Sports, Science and Technology
- 23K19900 Ministry of Education, Culture, Sports, Science and Technology
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Affiliation(s)
- Momoko Gyoten
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
| | - Yi Luo
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
- Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong 226001, China
| | - Rina Fujiwara-Tani
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
| | - Shiori Mori
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
| | - Ruiko Ogata
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
| | - Shingo Kishi
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
- Research Institute, Nozaki Tokushukai Hospital, 2-10-50 Tanigawa, Daito 574-0074, Osaka, Japan
| | - Hiroki Kuniyasu
- Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan; (M.G.); (Y.L.); (S.M.); (R.O.); (S.K.)
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14
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Ricco N, Kron SJ. Statins in Cancer Prevention and Therapy. Cancers (Basel) 2023; 15:3948. [PMID: 37568764 PMCID: PMC10417177 DOI: 10.3390/cancers15153948] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/29/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
Statins, a class of HMG-CoA reductase inhibitors best known for their cholesterol-reducing and cardiovascular protective activity, have also demonstrated promise in cancer prevention and treatment. This review focuses on their potential applications in head and neck cancer (HNC), a common malignancy for which established treatment often fails despite incurring debilitating adverse effects. Preclinical and clinical studies have suggested that statins may enhance HNC sensitivity to radiation and other conventional therapies while protecting normal tissue, but the underlying mechanisms remain poorly defined, likely involving both cholesterol-dependent and -independent effects on diverse cancer-related pathways. This review brings together recent discoveries concerning the anticancer activity of statins relevant to HNC, highlighting their anti-inflammatory activity and impacts on DNA-damage response. We also explore molecular targets and mechanisms and discuss the potential to integrate statins into conventional HNC treatment regimens to improve patient outcomes.
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Affiliation(s)
- Natalia Ricco
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, 08195 Barcelona, Spain;
| | - Stephen J. Kron
- Department of Molecular Genetics and Cell Biology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL 60637, USA
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15
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Sangande F, Agustini K, Budipramana K. Antihyperlipidemic mechanisms of a formula containing Curcuma xanthorrhiza, Sechium edule, and Syzigium polyanthum: In silico and in vitro studies. Comput Biol Chem 2023; 105:107907. [PMID: 37392529 DOI: 10.1016/j.compbiolchem.2023.107907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/14/2023] [Accepted: 06/17/2023] [Indexed: 07/03/2023]
Abstract
Herbal medicines are multi-component and can exhibit synergistic effects in the treatment of diseases. Sechium edule, Syzigium polyanthum, and Curcuma xanthorrhiza have been used in traditional medicine to reduce serum lipid levels. However, the molecular mechanism was not described clearly, especially as a mixture. Thus, we performed a network pharmacology study combined with molecular docking to find a rational explanation regarding the molecular mechanisms of this antihyperlipidemic formula. According to the network pharmacology study, we predicted that this extract mixture would act as an antihyperlipidemic agent by modulating several pathways including insulin resistance, endocrine resistance, and AMP-activated protein kinase (AMPK) signaling pathway. Based on the topology parameters, we identified 6 significant targets that play an important role in reducing lipid serum levels: HMG-CoA reductase (HMGCR), peroxisome proliferator-activated receptor alpha (PPARA), RAC-alpha serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP9), and tumor necrosis factor-alpha (TNF). Meanwhile, 8 compounds: β-sitosterol, bisdesmethoxycurcumin, cucurbitacin D, cucurbitacin E, myricetin, phloretin, quercitrin, and rutin were the compounds with a high degree, indicating that these compounds have a multitarget effect. Our consensus docking study revealed that HMGCR was the only protein targeted by all potential compounds, and rutin was the compound with the best consensus docking score for almost all targets. The in vitro study revealed that the extract combination could inhibit HMGCR with an IC50 value of 74.26 µg/mL, indicating that HMGCR inhibition is one of its antihyperlipidemic mechanisms.
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Affiliation(s)
- Frangky Sangande
- Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), Cibinong Science Center, Bogor 16915, Indonesia.
| | - Kurnia Agustini
- Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), Cibinong Science Center, Bogor 16915, Indonesia
| | - Krisyanti Budipramana
- Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Surabaya, Surabaya 60293, Indonesia
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16
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Li C, Wang F, Cui L, Li S, Zhao J, Liao L. Association between abnormal lipid metabolism and tumor. Front Endocrinol (Lausanne) 2023; 14:1134154. [PMID: 37305043 PMCID: PMC10248433 DOI: 10.3389/fendo.2023.1134154] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 05/05/2023] [Indexed: 06/13/2023] Open
Abstract
Metabolic Reprogramming is a sign of tumor, and as one of the three major substances metabolism, lipid has an obvious impact. Abnormal lipid metabolism is related to the occurrence of various diseases, and the proportion of people with abnormal lipid metabolism is increasing year by year. Lipid metabolism is involved in the occurrence, development, invasion, and metastasis of tumors by regulating various oncogenic signal pathways. The differences in lipid metabolism among different tumors are related to various factors such as tumor origin, regulation of lipid metabolism pathways, and diet. This article reviews the synthesis and regulatory pathways of lipids, as well as the research progress on cholesterol, triglycerides, sphingolipids, lipid related lipid rafts, adipocytes, lipid droplets, and lipid-lowering drugs in relation to tumors and their drug resistance. It also points out the limitations of current research and potential tumor treatment targets and drugs in the lipid metabolism pathway. Research and intervention on lipid metabolism abnormalities may provide new ideas for the treatment and survival prognosis of tumors.
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Affiliation(s)
- Chunyu Li
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
| | - Fei Wang
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
| | - Lili Cui
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
| | - Shaoxin Li
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
| | - Junyu Zhao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Institute of Nephrology, Jinan, China
- Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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17
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ERRα Up-Regulates Invadopodia Formation by Targeting HMGCS1 to Promote Endometrial Cancer Invasion and Metastasis. Int J Mol Sci 2023; 24:ijms24044010. [PMID: 36835419 PMCID: PMC9964422 DOI: 10.3390/ijms24044010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/06/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Estrogen-related receptor alpha (ERRα) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERRα in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERRα and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERRα and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERRα/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERRα and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERRα and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERRα and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERRα and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERRα promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial-mesenchymal transition pathway. Our findings suggest that ERRα and HMGCS1 are potential targets to suppress EC progression.
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18
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Use of Hypolipidemic Drugs and the Risk of Second Primary Malignancy in Colorectal Cancer Patients. Cancers (Basel) 2022; 14:cancers14071699. [PMID: 35406471 PMCID: PMC8997159 DOI: 10.3390/cancers14071699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Hypolipidemic drugs are among the most frequently prescribed medications in the Western world. Since many studies have indicated their role in carcinogenesis, this work aimed to investigate their association with the occurrence of a second primary malignancy in colorectal cancer survivors. The overall incidence of a second neoplasm was not linked to hypolipidemic medication; however, a subgroup analysis revealed a lower incidence of secondary neoplasia in statin users. When stratified by cancer types, a significant increase in gastric and bladder cancer was detected among colorectal cancer patients using hypolipidemic drugs. Survival outcomes in patients with early-stage colorectal carcinoma who suffered second cancer were significantly worse if treated with hypolipidemic drugs. Although our results do not provide evidence for a causative relationship between hypolipidemic medication and carcinogenesis, these correlations might steer the direction of tertiary prevention care towards specific risk factors shared between cardiovascular diseases and cancer. Abstract An increasing number of studies has brought evidence of the protective role of statin use against different types of cancer. However, data on their association with second primary malignancies (SPMs) are lacking. The purpose of this study was to determine the role of hypolipidemic treatment in the prevention of second primary cancer in colorectal cancer (CRC) survivors. We conducted a retrospective single-institution study of 1401 patients with newly diagnosed colorectal cancer from January 2003 to December 2016, with follow-up until December 2020. An SPM was detected in 301 patients (21%), and the incidence was significantly lower in patients with statin medication. However, stratification by cancer types revealed an increased incidence of bladder and gastric cancer in hypolipidemic users. A Kaplan−Meier analysis of early-stage CRC survivors with an SPM showed a significant survival benefit in patients without a history of hypolipidemic treatment. Despite the protective role of statins on overall second cancer incidence, these data indicate that CRC survivors treated with hypolipidemic drugs should be screened more cautiously for SPMs, especially for gastric and bladder cancer.
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