|
1
|
Ung J, Kassai M, Tan SF, Loughran TP, Feith DJ, Cabot MC. The Drug Transporter P-Glycoprotein and Its Impact on Ceramide Metabolism-An Unconventional Ally in Cancer Treatment. Int J Mol Sci 2024; 25:9825. [PMID: 39337312 PMCID: PMC11432138 DOI: 10.3390/ijms25189825] [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: 07/26/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/30/2024] Open
Abstract
The tumor-suppressor sphingolipid ceramide is recognized as a key participant in the cytotoxic mechanism of action of many types of chemotherapy drugs, including anthracyclines, Vinca alkaloids, the podophyllotoxin etoposide, taxanes, and the platinum drug oxaliplatin. These drugs can activate de novo synthesis of ceramide or stimulate the production of ceramide via sphingomyelinases to limit cancer cell survival. On the contrary, dysfunctional sphingolipid metabolism, a prominent factor in cancer survival and therapy resistance, blunts the anticancer properties of ceramide-orchestrated cell death pathways, especially apoptosis. Although P-glycoprotein (P-gp) is famous for its role in chemotherapy resistance, herein, we propose alternate interpretations and discuss the capacity of this multidrug transporter as a "ceramide neutralizer", an unwelcome event, highlighting yet another facet of P-gp's versatility in drug resistance. We introduce sphingolipid metabolism and its dysfunctional regulation in cancer, present a summary of factors that contribute to chemotherapy resistance, explain how P-gp "neutralizes" ceramide by hastening its glycosylation, and consider therapeutic applications of the P-gp-ceramide connection in the treatment of cancer.
Collapse
Affiliation(s)
- Johnson Ung
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA;
| | - Miki Kassai
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, The East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA;
| | - Su-Fern Tan
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; (S.-F.T.); (D.J.F.)
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Thomas P. Loughran
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; (S.-F.T.); (D.J.F.)
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - David J. Feith
- University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; (S.-F.T.); (D.J.F.)
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Myles C. Cabot
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, The East Carolina Diabetes and Obesity Institute, Greenville, NC 27834, USA;
| |
Collapse
|
|
2
|
Laface C, Ricci AD, Vallarelli S, Ostuni C, Rizzo A, Ambrogio F, Centonze M, Schirizzi A, De Leonardis G, D’Alessandro R, Lotesoriere C, Giannelli G. Autotaxin-Lysophosphatidate Axis: Promoter of Cancer Development and Possible Therapeutic Implications. Int J Mol Sci 2024; 25:7737. [PMID: 39062979 PMCID: PMC11277072 DOI: 10.3390/ijms25147737] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Autotaxin (ATX) is a member of the ectonucleotide pyrophosphate/phosphodiesterase (ENPP) family; it is encoded by the ENPP2 gene. ATX is a secreted glycoprotein and catalyzes the hydrolysis of lysophosphatidylcholine to lysophosphatidic acid (LPA). LPA is responsible for the transduction of various signal pathways through the interaction with at least six G protein-coupled receptors, LPA Receptors 1 to 6 (LPAR1-6). The ATX-LPA axis is involved in various physiological and pathological processes, such as angiogenesis, embryonic development, inflammation, fibrosis, and obesity. However, significant research also reported its connection to carcinogenesis, immune escape, metastasis, tumor microenvironment, cancer stem cells, and therapeutic resistance. Moreover, several studies suggested ATX and LPA as relevant biomarkers and/or therapeutic targets. In this review of the literature, we aimed to deepen knowledge about the role of the ATX-LPA axis as a promoter of cancer development, progression and invasion, and therapeutic resistance. Finally, we explored its potential application as a prognostic/predictive biomarker and therapeutic target for tumor treatment.
Collapse
Affiliation(s)
- Carmelo Laface
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Angela Dalia Ricci
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Simona Vallarelli
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Carmela Ostuni
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy
| | - Francesca Ambrogio
- Section of Dermatology and Venereology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Centonze
- Personalized Medicine Laboratory, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy;
| | - Annalisa Schirizzi
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Giampiero De Leonardis
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Rosalba D’Alessandro
- Laboratory of Experimental Oncology, National Institute of Gastroenterology, “IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy; (A.S.); (G.D.L.)
| | - Claudio Lotesoriere
- Medical Oncology Unit, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| |
Collapse
|
|
3
|
Hengst JA, Nduwumwami AJ, Sharma A, Yun JK. Fanning the Flames of Endoplasmic Reticulum (ER) Stress: Can Sphingolipid Metabolism Be Targeted to Enhance ER Stress-Associated Immunogenic Cell Death in Cancer? Mol Pharmacol 2024; 105:155-165. [PMID: 38164594 PMCID: PMC10877730 DOI: 10.1124/molpharm.123.000786] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 12/07/2023] [Accepted: 12/08/2023] [Indexed: 01/03/2024] Open
Abstract
The three arms of the unfolded protein response (UPR) surveil the luminal environment of the endoplasmic reticulum (ER) and transmit information through the lipid bilayer to the cytoplasm to alert the cell of stress conditions within the ER lumen. That same lipid bilayer is the site of de novo synthesis of phospholipids and sphingolipids. Thus, it is no surprise that lipids are modulated by and are modulators of ER stress. Given that sphingolipids have both prosurvival and proapoptotic effects, they also exert opposing effects on life/death decisions in the face of prolonged ER stress detected by the UPR. In this review, we will focus on several recent studies that demonstrate how sphingolipids affect each arm of the UPR. We will also discuss the role of sphingolipids in the process of immunogenic cell death downstream of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiating factor 2α (eIF2α) arm of the UPR. Furthermore, we will discuss strategies to target the sphingolipid metabolic pathway that could potentially act synergistically with agents that induce ER stress as novel anticancer treatments. SIGNIFICANCE STATEMENT: This review provides the readers with a brief discussion of the sphingolipid metabolic pathway and the unfolded protein response. The primary focus of the review is the mechanism(s) by which sphingolipids modulate the endoplasmic reticulum (ER) stress response pathways and the critical role of sphingolipids in the process of immunogenic cell death associated with the ER stress response.
Collapse
Affiliation(s)
- Jeremy A Hengst
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| | - Asvelt J Nduwumwami
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| | - Arati Sharma
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| | - Jong K Yun
- Departments of Pediatrics (J.A.H.) and Pharmacology (A.S., J.K.Y.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and Department of Drug Metabolism and Pharmacokinetics, National Center for Advancing Translational Science, Rockville, Maryland (A.J.N.)
| |
Collapse
|
|
4
|
Fisher-Wellman KH, Kassai M, Hagen JT, Neufer PD, Kester M, Loughran TP, Chalfant CE, Feith DJ, Tan SF, Fox TE, Ung J, Fabrias G, Abad JL, Sharma A, Golla U, Claxton DF, Shaw JJP, Bhowmick D, Cabot MC. Simultaneous Inhibition of Ceramide Hydrolysis and Glycosylation Synergizes to Corrupt Mitochondrial Respiration and Signal Caspase Driven Cell Death in Drug-Resistant Acute Myeloid Leukemia. Cancers (Basel) 2023; 15:1883. [PMID: 36980769 PMCID: PMC10046858 DOI: 10.3390/cancers15061883] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 03/10/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a "reset" would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3β, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an in vivo model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists.
Collapse
Affiliation(s)
- Kelsey H. Fisher-Wellman
- Department of Integrative Physiology and Metabolism, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA
- UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
| | - Miki Kassai
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - James T. Hagen
- Department of Integrative Physiology and Metabolism, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA
| | - P. Darrell Neufer
- Department of Integrative Physiology and Metabolism, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA
| | - Mark Kester
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- University of Virginia Cancer Center, Charlottesville, VA 22908, USA
| | - Thomas P. Loughran
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- University of Virginia Cancer Center, Charlottesville, VA 22908, USA
| | - Charles E. Chalfant
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- University of Virginia Cancer Center, Charlottesville, VA 22908, USA
- Department of Cell Biology, University of Virginia, Charlottesville, VA 22903, USA
- Research Service, Richmond Veterans Administration Medical Center, Richmond, VA 23298, USA
| | - David J. Feith
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- University of Virginia Cancer Center, Charlottesville, VA 22908, USA
| | - Su-Fern Tan
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
| | - Todd E. Fox
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
| | - Johnson Ung
- Department of Medicine, Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA 22903, USA
- University of Virginia Cancer Center, Charlottesville, VA 22908, USA
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Gemma Fabrias
- Research Unit on Bioactive Molecules (RUBAM), Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC), Spanish Council for Scientific Research (CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
| | - Jose’ Luis Abad
- Research Unit on Bioactive Molecules (RUBAM), Department of Biological Chemistry, Institute for Advanced Chemistry of Catalonia (IQAC), Spanish Council for Scientific Research (CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
| | - Arati Sharma
- Penn State Cancer Institute, Hershey, PA 17033, USA
- Department of Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Upendarrao Golla
- Penn State Cancer Institute, Hershey, PA 17033, USA
- Division of Hematology and Oncology, Penn State Cancer Institute, Hershey, PA 17033, USA
| | - David F. Claxton
- Division of Hematology and Oncology, Penn State Cancer Institute, Hershey, PA 17033, USA
| | - Jeremy J. P. Shaw
- University of Virginia Cancer Center, Charlottesville, VA 22908, USA
- Department of Experimental Pathology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
| | - Debajit Bhowmick
- Flow Cytometry Division, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Myles C. Cabot
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| |
Collapse
|
|
5
|
Implication of Ceramide Kinase/C1P in Cancer Development and Progression. Cancers (Basel) 2022; 14:cancers14010227. [PMID: 35008391 PMCID: PMC8750078 DOI: 10.3390/cancers14010227] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 12/28/2022] Open
Abstract
Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination.
Collapse
|
|
6
|
Piazzesi A, Afsar SY, van Echten‐Deckert G. Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance. Mol Oncol 2021; 15:3256-3279. [PMID: 34289244 PMCID: PMC8637577 DOI: 10.1002/1878-0261.13063] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 06/17/2021] [Accepted: 07/19/2021] [Indexed: 11/27/2022] Open
Abstract
Cancer development is a multistep process in which cells must overcome a series of obstacles before they can become fully developed tumors. First, cells must develop the ability to proliferate unchecked. Once this is accomplished, they must be able to invade the neighboring tissue, as well as provide themselves with oxygen and nutrients. Finally, they must acquire the ability to detach from the newly formed mass in order to spread to other tissues, all the while evading an immune system that is primed for their destruction. Furthermore, increased levels of inflammation have been shown to be linked to the development of cancer, with sites of chronic inflammation being a common component of tumorigenic microenvironments. In this Review, we give an overview of the impact of sphingolipid metabolism in cancers, from initiation to metastatic dissemination, as well as discussing immune responses and resistance to treatments. We explore how sphingolipids can either help or hinder the progression of cells from a healthy phenotype to a cancerous one.
Collapse
Affiliation(s)
- Antonia Piazzesi
- LIMES Institute for Membrane Biology and Lipid BiochemistryUniversity of BonnGermany
| | - Sumaiya Yasmeen Afsar
- LIMES Institute for Membrane Biology and Lipid BiochemistryUniversity of BonnGermany
| | | |
Collapse
|
|
7
|
Wu MH, Hui SC, Chen YS, Chiou HL, Lin CY, Lee CH, Hsieh YH. Norcantharidin combined with paclitaxel induces endoplasmic reticulum stress mediated apoptotic effect in prostate cancer cells by targeting SIRT7 expression. ENVIRONMENTAL TOXICOLOGY 2021; 36:2206-2216. [PMID: 34272796 DOI: 10.1002/tox.23334] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/15/2021] [Accepted: 07/07/2021] [Indexed: 06/13/2023]
Abstract
Prostate cancer (PCa), an extremely common malignancy in males, is the most prevalent disease in several countries. Norcantharidin (NCTD) has antiproliferation, antimetastasis, apoptosis, and autophagy effects in various tumor cells. Nevertheless, the antitumor effect of NCTD combined with paclitaxel (PTX), a chemotherapeutic drug, in PCa remains unknown. The cell growth, proliferative rate, cell cycle distribution, and cell death were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, colony formation assay, PI staining, and Annexin V/PI staining by flow cytomertry, whereas the mitochondrial membrane potential (MMP) and endoplasmic reticulum (ER) stress was evaluated using the MitoPotential assay and ER-ID red assay. We also evaluated the protein and mRNA expression of SIRTs by Western blotting and qRTPCR assay. Overexpression effectivity was measured by DNA transfection assay. Our study showed that cell viability and proliferative PC3 and DU145 rates were effectively inhibited after NCTD-PTX combination. We also found that NCTD-PTX combination treatment significantly enhance G2/M phase arrest, induction of cell death and ER stress, loss of MMP, and ER- or apoptotic-related protein expression. Furthermore, NCTD-PTX combination treatment was significantly decreasing the protein and mRNA expression of SIRT7 in PCa cells. Combination therapy effectively reduced cell viability, ER stress-mediated apoptosis and p-eIF2α/ATF4/CHOP/cleaved-PARP expression inhibition in SIRT7 overexpression of PCa cells. These results indicate that NCTD combined with PTX induces ER stress-mediated apoptosis of PCa cells by regulating the SIRT7 expression axis. Moreover, combination therapy may become a potential therapeutic strategy against human PCa.
Collapse
Affiliation(s)
- Min-Hua Wu
- Laboratory Department, Chung-Kang Branch, Cheng-Ching General Hospital, Taichung, Taiwan
- Department of Medicinal Botanicals and Health Applications, Da-Yeh University, Chunghua, Taiwan
| | - Su-Chun Hui
- Laboratory Department, Chung-Kang Branch, Cheng-Ching General Hospital, Taichung, Taiwan
| | - Yong-Syuan Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Hui-Ling Chiou
- School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
| | - Ching-Yi Lin
- Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chien-Hsing Lee
- Division of Pediatric Surgery, Department of Surgery, China Medical University Children's Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Yi-Hsien Hsieh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
8
|
Shamshiddinova M, Gulyamov S, Kim HJ, Jung SH, Baek DJ, Lee YM. A Dansyl-Modified Sphingosine Kinase Inhibitor DPF-543 Enhanced De Novo Ceramide Generation. Int J Mol Sci 2021; 22:ijms22179190. [PMID: 34502095 PMCID: PMC8431253 DOI: 10.3390/ijms22179190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 12/29/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) synthesized by sphingosine kinase (SPHK) is a signaling molecule, involved in cell proliferation, growth, differentiation, and survival. Indeed, a sharp increase of S1P is linked to a pathological outcome with inflammation, cancer metastasis, or angiogenesis, etc. In this regard, SPHK/S1P axis regulation has been a specific issue in the anticancer strategy to turn accumulated sphingosine (SPN) into cytotoxic ceramides (Cers). For these purposes, there have been numerous chemicals synthesized for SPHK inhibition. In this study, we investigated the comparative efficiency of dansylated PF-543 (DPF-543) on the Cers synthesis along with PF-543. DPF-543 deserved attention in strong cytotoxicity, due to the cytotoxic Cers accumulation by ceramide synthase (CerSs). DPF-543 exhibited dual actions on Cers synthesis by enhancing serine palmitoyltransferase (SPT) activity, and by inhibiting SPHKs, which eventually induced an unusual environment with a high amount of 3-ketosphinganine and sphinganine (SPA). SPA in turn was consumed to synthesize Cers via de novo pathway. Interestingly, PF-543 increased only the SPN level, but not for SPA. In addition, DPF-543 mildly activates acid sphingomyelinase (aSMase), which contributes a partial increase in Cers. Collectively, a dansyl-modified DPF-543 relatively enhanced Cers accumulation via de novo pathway which was not observed in PF-543. Our results demonstrated that the structural modification on SPHK inhibitors is still an attractive anticancer strategy by regulating sphingolipid metabolism.
Collapse
Affiliation(s)
- Maftuna Shamshiddinova
- College of Pharmacy, Chungbuk National University, Chungbuk 28160, Korea; (M.S.); (S.G.); (H.-J.K.); (S.-H.J.)
| | - Shokhid Gulyamov
- College of Pharmacy, Chungbuk National University, Chungbuk 28160, Korea; (M.S.); (S.G.); (H.-J.K.); (S.-H.J.)
| | - Hee-Jung Kim
- College of Pharmacy, Chungbuk National University, Chungbuk 28160, Korea; (M.S.); (S.G.); (H.-J.K.); (S.-H.J.)
| | - Seo-Hyeon Jung
- College of Pharmacy, Chungbuk National University, Chungbuk 28160, Korea; (M.S.); (S.G.); (H.-J.K.); (S.-H.J.)
| | - Dong-Jae Baek
- College of Pharmacy, Mokpo National University, Jeonnam 58628, Korea;
| | - Yong-Moon Lee
- College of Pharmacy, Chungbuk National University, Chungbuk 28160, Korea; (M.S.); (S.G.); (H.-J.K.); (S.-H.J.)
- Correspondence: ; Tel.: +82-43-261-2825
| |
Collapse
|
|
9
|
Ceramide Metabolism Enzymes-Therapeutic Targets against Cancer. ACTA ACUST UNITED AC 2021; 57:medicina57070729. [PMID: 34357010 PMCID: PMC8303233 DOI: 10.3390/medicina57070729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/07/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022]
Abstract
Sphingolipids are both structural molecules that are essential for cell architecture and second messengers that are involved in numerous cell functions. Ceramide is the central hub of sphingolipid metabolism. In addition to being the precursor of complex sphingolipids, ceramides induce cell cycle arrest and promote cell death and inflammation. At least some of the enzymes involved in the regulation of sphingolipid metabolism are altered in carcinogenesis, and some are targets for anticancer drugs. A number of scientific reports have shown how alterations in sphingolipid pools can affect cell proliferation, survival and migration. Determination of sphingolipid levels and the regulation of the enzymes that are implicated in their metabolism is a key factor for developing novel therapeutic strategies or improving conventional therapies. The present review highlights the importance of bioactive sphingolipids and their regulatory enzymes as targets for therapeutic interventions with especial emphasis in carcinogenesis and cancer dissemination.
Collapse
|
|
10
|
Weber DD, Thapa M, Aminzadeh-Gohari S, Redtenbacher AS, Catalano L, Feichtinger RG, Koelblinger P, Dallmann G, Emberger M, Kofler B, Lang R. Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts. Cancers (Basel) 2021; 13:434. [PMID: 33498757 PMCID: PMC7865782 DOI: 10.3390/cancers13030434] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/15/2021] [Accepted: 01/20/2021] [Indexed: 12/16/2022] Open
Abstract
Melanomas are genetically and metabolically heterogeneous, which influences therapeutic efficacy and contributes to the development of treatment resistance in patients with metastatic disease. Metabolite phenotyping helps to better understand complex metabolic diseases, such as melanoma, and facilitates the development of novel therapies. Our aim was to characterize the tumor and plasma metabolomes of mice bearing genetically different melanoma xenografts. We engrafted the human melanoma cell lines A375 (BRAF mutant), WM47 (BRAF mutant), WM3000 (NRAS mutant), and WM3311 (BRAF, NRAS, NF1 triple-wildtype) and performed a broad-spectrum targeted metabolomics analysis of tumor and plasma samples obtained from melanoma-bearing mice as well as plasma samples from healthy control mice. Differences in ceramide and phosphatidylcholine species were observed between melanoma subtypes irrespective of the genetic driver mutation. Furthermore, beta-alanine metabolism differed between melanoma subtypes and was significantly enriched in plasma from melanoma-bearing mice compared to healthy mice. Moreover, we identified beta-alanine, p-cresol sulfate, sarcosine, tiglylcarnitine, two dihexosylceramides, and one phosphatidylcholine as potential melanoma biomarkers in plasma. The present data reflect the metabolic heterogeneity of melanomas but also suggest a diagnostic biomarker signature for melanoma screening.
Collapse
Affiliation(s)
- Daniela D. Weber
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (D.D.W.); (S.A.-G.); (A.-S.R.); (L.C.); (R.G.F.)
| | - Maheshwor Thapa
- BIOCRATES Life Sciences AG, 6020 Innsbruck, Austria; (M.T.); (G.D.)
| | - Sepideh Aminzadeh-Gohari
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (D.D.W.); (S.A.-G.); (A.-S.R.); (L.C.); (R.G.F.)
| | - Anna-Sophia Redtenbacher
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (D.D.W.); (S.A.-G.); (A.-S.R.); (L.C.); (R.G.F.)
| | - Luca Catalano
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (D.D.W.); (S.A.-G.); (A.-S.R.); (L.C.); (R.G.F.)
| | - René G. Feichtinger
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (D.D.W.); (S.A.-G.); (A.-S.R.); (L.C.); (R.G.F.)
| | - Peter Koelblinger
- Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Guido Dallmann
- BIOCRATES Life Sciences AG, 6020 Innsbruck, Austria; (M.T.); (G.D.)
| | | | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria; (D.D.W.); (S.A.-G.); (A.-S.R.); (L.C.); (R.G.F.)
| | - Roland Lang
- Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria;
| |
Collapse
|
|
11
|
Fisher-Wellman KH, Hagen JT, Neufer PD, Kassai M, Cabot MC. On the nature of ceramide-mitochondria interactions - Dissection using comprehensive mitochondrial phenotyping. Cell Signal 2020; 78:109838. [PMID: 33212155 DOI: 10.1016/j.cellsig.2020.109838] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023]
Abstract
Sphingolipids are a unique class of lipids owing to their non-glycerol-containing backbone, ceramide, that is constructed from a long-chain aliphatic amino alcohol, sphinganine, to which a fatty acid is attached via an amide bond. Ceramide plays a star role in the initiation of apoptosis by virtue of its interactions with mitochondria, a control point for a downstream array of signaling cascades culminating in apoptosis. Many pathways converge on mitochondria to elicit mitochondrial outer membrane permeabilization (MOMP), a step that corrupts bioenergetic service. Although much is known regarding ceramides interaction with mitochondria and the ensuing cell signal transduction cascades, how ceramide impacts the elements of mitochondrial bioenergetic function is poorly understood. The objective of this review is to introduce the reader to sphingolipid metabolism, present a snapshot of mitochondrial respiration, elaborate on ceramides convergence on mitochondria and the upstream players that collaborate to elicit MOMP, and introduce a mitochondrial phenotyping platform that can be of utility in dissecting the fine-points of ceramide impact on cellular bioenergetics.
Collapse
Affiliation(s)
- Kelsey H Fisher-Wellman
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America.
| | - James T Hagen
- Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America
| | - P Darrell Neufer
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America
| | - Miki Kassai
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America
| | - Myles C Cabot
- Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, United States of America.
| |
Collapse
|
|
12
|
Tang X, Benesch MGK, Brindley DN. Role of the autotaxin-lysophosphatidate axis in the development of resistance to cancer therapy. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158716. [PMID: 32305571 DOI: 10.1016/j.bbalip.2020.158716] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/31/2020] [Accepted: 04/09/2020] [Indexed: 12/17/2022]
Abstract
Autotaxin (ATX) is a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidate (LPA), which signals through six G-protein coupled receptors (GPCRs). Signaling through LPA is terminated by its degradation by a family of three lipid phosphate phosphatases (LPPs). LPP1 also attenuates signaling downstream of the activation of LPA receptors and some other GPCRs. The ATX-LPA axis mediates a plethora of activities such as cell proliferation, survival, migration, angiogenesis and inflammation, which perform an important role in facilitating wound healing. This wound healing response is hijacked by cancers where there is decreased expression of LPP1 and LPP3 and increased expression of ATX. This maladaptive regulation of LPA signaling also causes chronic inflammation, which has been recognized as one of the hallmarks in cancer. The increased LPA signaling promotes cell survival and migration and attenuates apoptosis, which stimulates tumor growth and metastasis. The wound healing functions of increased LPA signaling also protect cancer cells from effects of chemotherapy and radiotherapy. In this review, we will summarize knowledge of the ATX-LPA axis and its role in the development of resistance to chemotherapy and radiotherapy. We will also offer insights for developing strategies of targeting ATX-LPA axis as a novel part of cancer treatment. This article is part of a Special Issue entitled Lysophospholipids and their receptors: New data and new insights into their function edited by Susan Smyth, Viswanathan Natarajan and Colleen McMullen.
Collapse
Affiliation(s)
- Xiaoyun Tang
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada
| | - Matthew G K Benesch
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada; Discipline of Surgery, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador A1B 3V6, Canada
| | - David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton T6G 2S2, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton T6G 2S2, Canada.
| |
Collapse
|
|
13
|
Shih CM, Chen CC, Chu CK, Wang KH, Huang CY, Lee AW. The Roles of Lipoprotein in Psoriasis. Int J Mol Sci 2020; 21:ijms21030859. [PMID: 32013194 PMCID: PMC7036823 DOI: 10.3390/ijms21030859] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 01/15/2020] [Accepted: 01/26/2020] [Indexed: 02/07/2023] Open
Abstract
The association between psoriasis and cardiovascular disease risk has been supported by recent epidemiological data. Patients with psoriasis have an increased adjusted relative risk for myocardial infarction. As such, the cardiovascular risk conferred by severe psoriasis may be comparable to what is seen with other well-established risk factors, such as diabetes mellitus. Previous studies demonstrated that low-density lipoprotein (LDL) plays critical roles during atherogenesis. It may be caused by the accumulation of macrophages and lipoprotein in the vessel wall. Oxidized LDL (ox-LDL) stimulates the expression of adhesion molecules, such as ICAM-1 and VCAM-1, on endothelial cells and increases the attachment of mononuclear cells and the endothelium. Even though previous evidence demonstrated that psoriasis patients have tortuous and dilated blood vessels in the dermis, which results in the leakage of ox-LDL, the leaked ox-LDL may increase the expression of adhesion molecules and cytokines, and disturb the static balance of osmosis. Therefore, exploration of the relationship between hyperlipidemia and psoriasis may be another novel treatment option for psoriasis and may represent the most promising strategy.
Collapse
Affiliation(s)
- Chun-Ming Shih
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (C.-M.S.); (C.-Y.H.)
- Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Chang-Cyuan Chen
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
| | - Chen-Kuo Chu
- Department of Emergency Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan;
| | - Kuo-Hsien Wang
- Department of Dermatology, Taipei Medical University Hospital, Taipei 11031, Taiwan;
| | - Chun-Yao Huang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (C.-M.S.); (C.-Y.H.)
- Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
| | - Ai-Wei Lee
- Cardiovascular Research Center, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Correspondence: ; Tel.: +(886-2)-2736-1661 (ext. 3255)
| |
Collapse
|
|
14
|
Kim HY, Jin H, Bae J, Choi HK. Metabolic and lipidomic investigation of the antiproliferative effects of coronatine against human melanoma cells. Sci Rep 2019; 9:3140. [PMID: 30816283 PMCID: PMC6395766 DOI: 10.1038/s41598-019-39990-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 02/04/2019] [Indexed: 12/22/2022] Open
Abstract
Melanoma is the most aggressive form of skin cancer, with metastatic melanoma being refractory to currently available conventional therapies. In this study, we evaluated the inhibitory effect of coronatine (COR) on the proliferation of metastatic melanoma cells. COR inhibited the proliferation of melanoma cells but negligibly affected the proliferation of normal melanocytes. Comparative metabolic and lipidomic profiling using gas chromatography-mass spectrometry and direct infusion-mass spectrometry was performed to investigate COR-induced metabolic changes. These analyses identified 33 metabolites and 82 lipids. Of these, the levels of lactic acid and glutamic acid, which are involved in energy metabolism, significantly decreased in COR-treated melanoma cells. Lipidomic profiling indicated that ceramide levels increased in COR-treated melanoma cells, suggesting that ceramides could function as a suppressor of cancer cell proliferation. In contrast, the levels of phosphatidylinositol (PI) species, including PI 16:0/18:0, 16:0/18:1, 18:0/18:0, and 18:0/18:1, which were found to be potential biomarkers of melanoma metastasis in our previous study, were lower in the COR-treated cells than in control cells. The findings of metabolomic and lipidomic profiling performed in the present study provide new insights on the anticancer mechanisms of COR and can be used to apply COR in cancer treatment.
Collapse
Affiliation(s)
- Hye-Youn Kim
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Hanyong Jin
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Jeehyeon Bae
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Hyung-Kyoon Choi
- College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
| |
Collapse
|
|
15
|
Martinho N, Santos TCB, Florindo HF, Silva LC. Cisplatin-Membrane Interactions and Their Influence on Platinum Complexes Activity and Toxicity. Front Physiol 2019; 9:1898. [PMID: 30687116 PMCID: PMC6336831 DOI: 10.3389/fphys.2018.01898] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/18/2018] [Indexed: 01/22/2023] Open
Abstract
Cisplatin and other platinum(II) analogs are widely used in clinical practice as anti-cancer drugs for a wide range of tumors. The primary mechanism by which they exert their action is through the formation of adducts with genomic DNA. However, multiple cellular targets by platinum(II) complexes have been described. In particular, the early events occurring at the plasma membrane (PM), i.e., platinum-membrane interactions seem to be involved in the uptake, cytotoxicity and cell-resistance to cisplatin. In fact, PM influences signaling events, and cisplatin-induced changes on membrane organization and fluidity were shown to activate apoptotic pathways. This review critically discusses the sequence of events caused by lipid membrane-platinum interactions, with emphasis on the mechanisms that lead to changes in the biophysical properties of the membranes (e.g., fluidity and permeability), and how these correlate with sensitivity and resistance phenotypes of cells to platinum(II) complexes.
Collapse
Affiliation(s)
- Nuno Martinho
- iMed.ULisboa - Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
| | - Tânia C B Santos
- iMed.ULisboa - Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal.,Centro de Química-Física Molecular, Institute of Nanoscience and Nanotechnology and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Helena F Florindo
- iMed.ULisboa - Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal
| | - Liana C Silva
- iMed.ULisboa - Research Institute for Medicines, Faculdade de Farmácia, Universidade de Lisboa, Lisbon, Portugal.,Centro de Química-Física Molecular, Institute of Nanoscience and Nanotechnology and IBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| |
Collapse
|
|
16
|
Abstract
Chemotherapy resistance, inherent or acquired, represents a serious barrier to the successful treatment of cancer. Although drug efflux, conducted by plasma membrane-resident proteins, detoxification enzymes, cell death inhibition, and DNA damage repair are ensemble players in this unwanted biology, a full understanding of the many in concert molecular mechanisms driving drug resistance is lacking. Recent discoveries in sphingolipid (SL) metabolism have provided significant insight into the role of these lipids in cancer growth; however, considerably less is known with respect to SLs and the drug-resistant phenotype. One exception here is enhanced ceramide glycosylation, a hallmark of multidrug resistance that is believed responsible, in part, for diminishing ceramides tumor-suppressor potential. This chapter will review various aspects of SL biology that relate to chemotherapy resistance and extend this topic to acknowledge the role of chemotherapy selection pressure in promoting dysregulated SL metabolism, a characteristic in cancer and an exploitable target for therapy.
Collapse
|
|
17
|
Abstract
The sphingolipid family of lipids modulate several cellular processes, including proliferation, cell cycle regulation, inflammatory signaling pathways, and cell death. Several members of the sphingolipid pathway have opposing functions and thus imbalances in sphingolipid metabolism result in deregulated cellular processes, which cause or contribute to diseases and disorders in humans. A key cellular process regulated by sphingolipids is apoptosis, or programmed cell death. Sphingolipids play an important role in both extrinsic and intrinsic apoptotic pathways depending on the stimuli, cell type and cellular response to the stress. During mitochondrial-mediated apoptosis, multiple pathways converge on mitochondria and induce mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of intermembrane space proteins such as cytochrome c and Apaf1 into the cytosol where they activate the caspases and DNases that execute cell death. The precise molecular components of the pore(s) responsible for MOMP are unknown, but sphingolipids are thought to play a role. Here, we review evidence for a role of sphingolipids in the induction of mitochondrial-mediated apoptosis with a focus on potential underlying molecular mechanisms by which altered sphingolipid metabolism indirectly or directly induce MOMP. Data available on these mechanisms is reviewed, and the focus and limitations of previous and current studies are discussed to present important unanswered questions and potential future directions.
Collapse
Affiliation(s)
- Gauri A Patwardhan
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA
| | - Levi J Beverly
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.,Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.,James Graham Brown Cancer Center, University of Louisville, 505 South Hancock Street, Clinical and Translational Research Building, Room 203, Louisville, KY, 40202, USA
| | - Leah J Siskind
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA. .,James Graham Brown Cancer Center, University of Louisville, 505 South Hancock Street, Clinical and Translational Research Building, Room 203, Louisville, KY, 40202, USA.
| |
Collapse
|
|
18
|
Choi J, Park JG, Ali MS, Choi SJ, Baek KH. Systematic Analysis of the Anticancer Agent Taxol-Producing Capacity in Colletotrichum Species and Use of the Species for Taxol Production. MYCOBIOLOGY 2016; 44:105-11. [PMID: 27433121 PMCID: PMC4945537 DOI: 10.5941/myco.2016.44.2.105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/25/2016] [Accepted: 06/23/2016] [Indexed: 06/06/2023]
Abstract
Paclitaxel (taxol) has long been used as a potent anticancer agent for the treatment of many cancers. Ever since the fungal species Taxomyces andreanae was first shown to produce taxol in 1993, many endophytic fungal species have been recognized as taxol accumulators. In this study, we analyzed the taxol-producing capacity of different Colletotrichum spp. to determine the distribution of a taxol biosynthetic gene within this genus. Distribution of the taxadiene synthase (TS) gene, which cyclizes geranylgeranyl diphosphate to produce taxadiene, was analyzed in 12 Colletotrichum spp., of which 8 were found to contain the unique skeletal core structure of paclitaxel. However, distribution of the gene was not limited to closely related species. The production of taxol by Colletotrichum dematium, which causes pepper anthracnose, depended on the method in which the fungus was stored, with the highest production being in samples stored under mineral oil. Based on its distribution among Colletotrichum spp., the TS gene was either integrated into or deleted from the bacterial genome in a species-specific manner. In addition to their taxol-producing capacity, the simple genome structure and easy gene manipulation of these endophytic fungal species make them valuable resources for identifying genes in the taxol biosynthetic pathway.
Collapse
Affiliation(s)
- Jinhee Choi
- Institute of Biotechnology, Yeungnam University, Gyeongsan 38541, Korea.; Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Jae Gyu Park
- Pohang Center for Evaluation Biomaterials (POCEB), Pohang Technopark Foundation, Pohang 37668, Korea
| | - Md Sarafat Ali
- Institute of Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| | - Seong-Jin Choi
- Department of Biotechnology, Catholic University of Daegu, Gyeongsan 38430, Korea
| | - Kwang-Hyun Baek
- Department of Biotechnology, Yeungnam University, Gyeongsan 38541, Korea
| |
Collapse
|
|
19
|
Hajj C, Becker-Flegler KA, Haimovitz-Friedman A. Novel mechanisms of action of classical chemotherapeutic agents on sphingolipid pathways. Biol Chem 2016; 396:669-79. [PMID: 25719313 DOI: 10.1515/hsz-2014-0302] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 02/12/2015] [Indexed: 12/15/2022]
Abstract
The prevailing mechanisms of action of traditional chemotherapeutic agents have been challenged by sphingolipid cancer research. Many studies have shown that ceramide generation in response to cytotoxic agents is central to tumor cell death. Ceramide can be generated either via hydrolysis of cell-membrane sphingomyelin by sphingomyelinases, hydrolysis of cerebrosides, or via de novo synthesis by ceramide synthases. Ceramide can act as a second messenger for apoptosis, senescence or autophagy. Inherent or acquired alterations in the sphingolipid pathway can account for resistance to the classic chemotherapeutic agents. In particular, it has been shown that activation of the acid ceramidase can lead to the formation of sphingosine 1-phosphate, which then antagonizes ceramide signaling by initiating a pro-survival signaling pathway. Furthermore, ceramide glycosylation catalyzed by glucosylceramide synthase converts ceramide to glucosylceramide, thus eliminating ceramide and consequently protecting cancer cells from apoptosis. In this review, we describe the effects of some of the most commonly used chemotherapeutic agents on ceramide generation, with a particular emphasis on strategies used to enhance the efficacy of these agents.
Collapse
|
|
20
|
Abstract
Studies over the past two decades have identified ceramide as a multifunctional central molecule in the sphingolipid biosynthetic pathway. Given its diverse tumor suppressive activities, molecular understanding of ceramide action will produce fundamental insights into processes that limit tumorigenesis and may identify key molecular targets for therapeutic intervention. Ceramide can be activated by a diverse array of stresses such as heat shock, genotoxic damage, oxidative stress and anticancer drugs. Ceramide triggers a variety of tumor suppressive and anti-proliferative cellular programs such as apoptosis, autophagy, senescence, and necroptosis by activating or repressing key effector molecules. Defects in ceramide generation and metabolism in cancer contribute to tumor cell survival and resistance to chemotherapy. The potent and versatile anticancer activity profile of ceramide has motivated drug development efforts to (re-)activate ceramide in established tumors. This review focuses on our current understanding of the tumor suppressive functions of ceramide and highlights the potential downstream targets of ceramide which are involved in its tumor suppressive action.
Collapse
|
|
21
|
del Solar V, Lizardo D, Li N, Hurst J, Brais C, Atilla-Gokcumen G. Differential Regulation of Specific Sphingolipids in Colon Cancer Cells during Staurosporine-Induced Apoptosis. ACTA ACUST UNITED AC 2015; 22:1662-70. [DOI: 10.1016/j.chembiol.2015.11.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 11/02/2015] [Accepted: 11/06/2015] [Indexed: 01/06/2023]
|
|
22
|
Morad SAF, Cabot MC. Tamoxifen regulation of sphingolipid metabolism--Therapeutic implications. Biochim Biophys Acta Mol Cell Biol Lipids 2015; 1851:1134-45. [PMID: 25964209 DOI: 10.1016/j.bbalip.2015.05.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 04/23/2015] [Accepted: 05/04/2015] [Indexed: 12/25/2022]
Abstract
Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid metabolism. More specifically, tamoxifen inhibits ceramide glycosylation, and enzymatic step that can adventitiously support the influential tumor-suppressor properties of ceramide, the aliphatic backbone of sphingolipids. Additionally, tamoxifen and metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, have been shown to inhibit ceramide hydrolysis by the enzyme acid ceramidase. This particular intervention slows ceramide destruction and thereby depresses formation of sphingosine 1-phosphate, a mitogenic sphingolipid with cancer growth-promoting properties. As ceramide-centric therapies are becoming appealing clinical interventions in the treatment of cancer, agents like tamoxifen that can retard the generation of mitogenic sphingolipids and buffer ceramide clearance via inhibition of glycosylation, take on new importance. In this review, we present an abridged, lay introduction to sphingolipid metabolism, briefly chronicle tamoxifen's history in the clinic, examine studies that demonstrate the impact of triphenylethylenes on sphingolipid metabolism in cancer cells, and canvass works relevant to the use of tamoxifen as adjuvant to drive ceramide-centric therapies in cancer treatment. The objective is to inform the readership of what could be a novel, off-label indication of tamoxifen and structurally-related triphenylethylenes, an indication divorced from estrogen receptor status and one with application in drug resistance.
Collapse
Affiliation(s)
- Samy A F Morad
- Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC 27834, USA; East Carolina Diabetes and Obesity Institute, 115 Heart Drive, Greenville, NC 27834, USA; Department of Pharmacology, Faculty of Veterinary Medicine, South Valley University, Qena 83523, Egypt
| | - Myles C Cabot
- Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC 27834, USA; East Carolina Diabetes and Obesity Institute, 115 Heart Drive, Greenville, NC 27834, USA.
| |
Collapse
|
|
23
|
New Insights into Antimetastatic and Antiangiogenic Effects of Cannabinoids. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2015; 314:43-116. [DOI: 10.1016/bs.ircmb.2014.10.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
|
|
24
|
Wang S, Qiu J, Shi Z, Wang Y, Chen M. Nanoscale drug delivery for taxanes based on the mechanism of multidrug resistance of cancer. Biotechnol Adv 2014; 33:224-241. [PMID: 25447422 DOI: 10.1016/j.biotechadv.2014.10.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/15/2014] [Accepted: 10/23/2014] [Indexed: 02/07/2023]
Abstract
Taxanes are one type of the most extensively used chemotherapeutic agents to treat cancers. However, their clinical use is severely limited by intrinsic and acquired resistance. A diverse variety of mechanisms has been implicated about taxane resistance, such as alterations of drug targets, overexpression of efflux transporters, defective apoptotic machineries, and barriers in drug transport. The deepening understanding of molecular mechanisms of taxane resistance has spawned a number of targets for reversing resistance. However, circumvention of taxane resistance would not only possess therapeutic potential, but also face with clinical challenge, which accelerates the development of optimal nanoscale delivery systems. This review highlights the current understanding on the mechanisms of taxane resistance, and provides a comprehensive analysis of various nanoscale delivery systems to reverse taxane resistance.
Collapse
Affiliation(s)
- Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Jiange Qiu
- Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Zhi Shi
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China; Department of Cell Biology and Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
| | - Yitao Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Meiwan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.
| |
Collapse
|
|
25
|
Siow D, Sunkara M, Morris A, Wattenberg B. Regulation of de novo sphingolipid biosynthesis by the ORMDL proteins and sphingosine kinase-1. Adv Biol Regul 2014; 57:42-54. [PMID: 25319495 DOI: 10.1016/j.jbior.2014.09.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 09/03/2014] [Accepted: 09/04/2014] [Indexed: 12/11/2022]
Abstract
Sphingolipids are a diverse set of structurally and metabolically related lipids that have numerous functions in cell structure and signaling. The regulation of these lipids is critical for normal cell function and disregulation has been implicated in pathophysiological conditions such as cancer and inflammation. Here we examine control of the initiating, and rate limiting, enzyme in sphingolipid biosynthesis, serine palmitoyltransferase (SPT). We find that de novo synthesis of sphingolipid is stimulated by a number of cancer chemotherapeutics, suggesting that this may be an important aspect of their cytotoxic effects. The three ORMDL proteins are membrane proteins of the endoplasmic reticulum related to the yeast Orm proteins, which have been shown to be homeostatic regulators of SPT. We find that the ORMDL proteins are also negative regulators of SPT that transmit cellular levels of sphingolipids to SPT. The three isoforms have redundant functions in this system. The sphingosine kinases (sphingosine kinase-1 and -2) phosphorylate both sphingosine, which is released from ceramide, but also dihydrosphingosine, which is in the de novo biosynthetic pathway. We therefore examined the role of the sphingosine kinases in controlling de novo ceramide biosynthesis and find that sphingosine kinase-1 does indeed act as a negative regulator of this pathway. This establishes that sphingosine kinase, in addition to producing sphingosine-1-phosphate as a signaling molecule, also consumes dihydrosphingosine to regulate ceramide synthesis. Our studies demonstrate that there are multiple mechanisms of regulation of SPT and suggest that these regulators are important mediators of cell stress responses.
Collapse
Affiliation(s)
- Deanna Siow
- James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA
| | - Manjula Sunkara
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky Lexington, Lexington, KY 40536, USA; Department of Veterans Affairs Medical Center, Lexington, KY, USA
| | - Andrew Morris
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky Lexington, Lexington, KY 40536, USA; Department of Veterans Affairs Medical Center, Lexington, KY, USA
| | - Binks Wattenberg
- James Graham Brown Cancer Center, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 505 South Hancock St., Louisville, KY 40202, USA.
| |
Collapse
|
|
26
|
Hasan MM, Kim HS, Jeon JH, Kim SH, Moon B, Song JY, Shim SH, Baek KH. Metabolic engineering of Nicotiana benthamiana for the increased production of taxadiene. PLANT CELL REPORTS 2014; 33:895-904. [PMID: 24463610 DOI: 10.1007/s00299-014-1568-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 01/08/2014] [Accepted: 01/09/2014] [Indexed: 05/03/2023]
Abstract
We report the production of taxadiene by transformation of N. benthamiana with a taxadiene synthase gene. The production was significantly increased by an elicitor treatment or metabolic pathway shunting. Paclitaxel (Taxol(®)) was first isolated from the bark of the pacific yew tree as an anticancer agent and has been used extensively to treat various types of cancer. Taxadiene, the first committed product of paclitaxel synthesis is cyclized from geranylgeranyl diphosphate (GGPP), and further complex hydroxylation and acylation processes of the unique taxane core skeleton produce paclitaxel. To accomplish de novo production of taxadiene, we transformed Nicotiana benthamiana with a taxadiene synthase (TS) gene. The introduced TS gene under the transcriptional control of the CaMV 35S promoter was constitutively expressed in N. benthamiana, and the de novo production of taxadiene was confirmed by mass spectroscopy profiling. Transformed N. benthamiana homozygous lines produced 11-27 μg taxadiene/g of dry weight. The highest taxadiene production line TSS-8 was further treated with an elicitor, methyl jasmonate, and metabolic pathway shunting by suppression of the phytoene synthase gene expression which resulted in accumulation of increased taxadiene accumulation by 1.4- or 1.9-fold, respectively. In summary, we report that the production of taxadiene in N. benthamiana was possible by the ectopic expression of the TS gene, and higher accumulation of taxadiene could be achieved by elicitor treatment or metabolic pathway shunting of the terpenoid pathway.
Collapse
Affiliation(s)
- Md Mohidul Hasan
- School of Biotechnology, Yeungnam University, Gyeongbuk, Gyeongsan, 712-749, Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Pan Z, Avila A, Gollahon L. Paclitaxel induces apoptosis in breast cancer cells through different calcium--regulating mechanisms depending on external calcium conditions. Int J Mol Sci 2014; 15:2672-94. [PMID: 24549172 PMCID: PMC3958875 DOI: 10.3390/ijms15022672] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 02/10/2014] [Accepted: 02/11/2014] [Indexed: 12/19/2022] Open
Abstract
Previously, we reported that endoplasmic reticulum calcium stores were a direct target for paclitaxel initiation of apoptosis. Furthermore, the actions of paclitaxel attenuated Bcl-2 resistance to apoptosis through endoplasmic reticulum-mediated calcium release. To better understand the calcium-regulated mechanisms of paclitaxel-induced apoptosis in breast cancer cells, we investigated the role of extracellular calcium, specifically; whether influx of extracellular calcium contributed to and/or was necessary for paclitaxel-induced apoptosis. Our results demonstrated that paclitaxel induced extracellular calcium influx. This mobilization of extracellular calcium contributed to subsequent cytosolic calcium elevation differently, depending on dosage. Under normal extracellular calcium conditions, high dose paclitaxel induced apoptosis-promoting calcium influx, which did not occur in calcium-free conditions. In the absence of extracellular calcium an “Enhanced Calcium Efflux” mechanism in which high dose paclitaxel stimulated calcium efflux immediately, leading to dramatic cytosolic calcium decrease, was observed. In the absence of extracellular calcium, high dose paclitaxel’s stimulatory effects on capacitative calcium entry and apoptosis could not be completely restored. Thus, normal extracellular calcium concentrations are critical for high dose paclitaxel-induced apoptosis. In contrast, low dose paclitaxel mirrored controls, indicating that it occurs independent of extracellular calcium. Thus, extracellular calcium conditions only affect efficacy of high dose paclitaxel-induced apoptosis.
Collapse
Affiliation(s)
- Zhi Pan
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
| | - Andrew Avila
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
| | - Lauren Gollahon
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
| |
Collapse
|
|
28
|
Khalkhali-Ellis Z, Hendrix MJC. Two Faces of Cathepsin D: Physiological Guardian Angel and Pathological Demon. ACTA ACUST UNITED AC 2014; 6. [PMID: 25663755 PMCID: PMC4318633 DOI: 10.4172/0974-8369.1000206] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived “house keeping” function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original “housekeeping” role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD’s post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the “site-specific” function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD’s association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients.
Collapse
Affiliation(s)
- Zhila Khalkhali-Ellis
- Stanley Manne Children's Research Institute, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, Illinois, 60614-3394, USA
| | - Mary J C Hendrix
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 2300 Children's Plaza, Box 222, Chicago, Illinois, 60614-3394, USA
| |
Collapse
|
|
29
|
Korbelik M, Zhang W, Saw KM, Szulc ZM, Bielawska A, Separovic D. Cationic ceramides and analogues, LCL30 and LCL85, as adjuvants to photodynamic therapy of tumors. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2013; 126:72-7. [PMID: 23911762 DOI: 10.1016/j.jphotobiol.2013.06.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2013] [Revised: 06/01/2013] [Accepted: 06/22/2013] [Indexed: 11/18/2022]
Abstract
Photodynamic therapy (PDT) is known to alter the expression of various genes in treated cells. This prompted us to examine the activity of genes encoding two important enzymes in sphingolipid (SL) metabolism, dihydroceramide desaturase (DES) and sphingosine kinase (SPHK), in mouse SCCVII tumor cells treated by PDT using either the porphyrin-based photosensitizer Photofrin or silicon phthalocyanine Pc4. The results revealed that PDT induced an upregulation in the expression of two major isoforms of both genes (DES1 and DES2 as well as SPHK1 and SPHK2). While the changes were generally moderate (2-3-fold gains), the increase in DES2 expression was more pronounced and it was much greater with Photofrin-PDT than with Pc4-PDT (over 23-fold vs. less than 5-fold). Combining either Photofrin-PDT or Pc4-PDT with the cationic C16-ceramide LCL30 (20mg/kg i.p.) for treatment of subcutaneously growing SCCVII tumors rendered important differences in the therapy outcome. Photofrin-PDT, used at a dose that attained good initial response but no tumor cures, produced 50% cures when combined with a single LCL30 treatment. In contrast, the same LCL30 treatment combined with Pc4-PDT had no significant effect on tumor response. The optimal timing of LCL30 injection was immediately after Photofrin-PDT. The therapeutic benefit was lost when LCL30 was given in two 20mg/kg injections encompassing intervals before and after PDT. LCL85, the cationic B13 ceramide analogue and SL-modulating agent, also increased cure rates of Photofrin-PDT treated tumors, but the therapeutic benefit was less pronounced than with LCL30. These results with LCL30 and LCL85, and our previous findings for LCL29 (another SL analogue), assert the potential of SLs for use as adjuvants to augment the efficacy of PDT-mediated tumor destruction.
Collapse
|
|
30
|
Acid ceramidase induces sphingosine kinase 1/S1P receptor 2-mediated activation of oncogenic Akt signaling. Oncogenesis 2013; 2:e49. [PMID: 23732709 PMCID: PMC3740300 DOI: 10.1038/oncsis.2013.14] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Acid ceramidase (AC) is overexpressed in most prostate tumors and confers oncogenic phenotypes to prostate cancer cells. AC modulates the cellular balance between ceramide, sphingosine and sphingosine 1-phosphate (S1P). These bioactive sphingolipids have diverse, powerful and often oppositional impacts on cell signaling, including the activation status of the oncogenic kinase Akt. Our studies show that AC expression correlates with phosphorylation of Akt in human prostate tumors, and elevation of phosphorylated Akt in tumor versus patient-matched benign tissue is contingent upon AC elevation. Investigation of the mechanism for AC-induced Akt activation revealed that AC activates Akt through sphingosine kinase 1 (SphK1)-derived generation of S1P. This signaling pathway proceeds through S1P receptor 2 (S1PR2)-dependent stimulation of PI3K. Functionally, AC-overexpressing cells are insensitive to cytotoxic chemotherapy, however, these cells are more susceptible to targeted inhibition of Akt. AC-overexpressing cells proliferate more rapidly than control cells and form more colonies in soft agar; however, these effects are profoundly sensitive to Akt inhibition, demonstrating increased dependence on Akt signaling for the oncogenic phenotypes of AC-overexpressing cells. These observations may have clinical implications for targeted therapy as PI3K and Akt inhibitors emerge from clinical trials.
Collapse
|
|
31
|
Best C, Calianese D, Szulak K, Cammarata G, Brum G, Carbone T, Still E, Higgins K, Ji F, DI W, Wanebo H, Wan Y. Paclitaxel disrupts polarized entry of membrane-permeable C6 ceramide into ovarian cancer cells resulting in synchronous induction of cell death. Oncol Lett 2013; 5:1854-1858. [PMID: 23833655 PMCID: PMC3701061 DOI: 10.3892/ol.2013.1305] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 03/21/2013] [Indexed: 11/05/2022] Open
Abstract
Exogenous cell-permeable C6 ceramide has been demonstrated to act synergistically with chemotherapeutic drugs, including paclitaxel, cisplatin, doxorubicin and the histone deacetylase inhibitor, trichostatin A, to induce cell death in a variety of cancer cells. We previously demonstrated that C6 ceramide and paclitaxel function synergistically to induce ovarian cancer cell death via modulation of the PI3/AKT cell survival pathway. In the present study, the entry pattern of C6 ceramide into ovarian cancer cells was investigated using fluorescent short chain C6-NBD sphingomyelin (C6-NBD). Confocal microscopy revealed that C6-NBD enters the cells in a polarized pattern, characterized by marked signals at one cellular end, representing a likely mitosis initiation site. Pretreatment of the cells with filipin, an inhibitor of the lipid raft/caveolae endocytosis pathway, decreases C6-NBD entry into the cells. A pretreatment with the water channel inhibitor, CuSO4, was also found to reduce the entry of C6-NBD. Notably, the pretreatment with paclitaxel was shown to disrupt the polarized entry of C6-NBD into the cells, resulting in an even distribution of C6-NBD in the cytoplasm. In addition, the pretreatment of the cells with paclitaxel destabilized the cytoskeletal proteins, releasing an increased number of short tubulin fragments. The results of the present study indicate that C6 ceramide preferentially enters the cells via a predetermined initiation site of mitosis. In addition to diffusion, short chain C6 ceramide may also enter cells via water channels and caveolae-mediated endocytosis. Paclitaxel disrupts the cell cytoskeleton and induces an even distribution of C6 ceramide in the cytoplasm resulting in synergistic ovarian cancer cell death.
Collapse
Affiliation(s)
- Charles Best
- Department of Biology, Providence College, Providence, RI 02918, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Yao C, Wei JJ, Wang ZY, Ding HM, Li D, Yan SC, Yang YJ, Gu ZP. Perifosine induces cell apoptosis in human osteosarcoma cells: new implication for osteosarcoma therapy? Cell Biochem Biophys 2013; 65:217-27. [PMID: 23015227 DOI: 10.1007/s12013-012-9423-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Despite the advances of adjuvant chemotherapy and significant improvement of survival, the prognosis for patients with osteosarcoma is generally poor. The search for more effective anti-osteosarcoma agents is necessary and urgent. Here we report that perifosine induces cell apoptosis and growth inhibition in cultured human osteosarcoma cells. Perifosine blocks Akt/mTOR complex 1 (mTORC1) signaling, while promoting caspase-3, c-Jun N-terminal kinases (JNK), and p53 activation. Further, perifosine inhibits survivin expression probably by disrupting its association with heat shock protein-90 (HSP-90). These signaling changes together were responsible for a marked increase of osteosarcoma cell apoptosis and growth inhibition. Finally, we found that a low dose of perifosine enhanced etoposide- or doxorubicin-induced anti-OS cells activity. The results together suggest that perifosine might be used as a novel and effective anti-osteosarcoma agent.
Collapse
Affiliation(s)
- Chen Yao
- Department of Orthopedics, BenQ Medical Center, Nanjing Medical University, Nanjing, Jiangsu, China
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Morad SAF, Madigan JP, Levin JC, Abdelmageed N, Karimi R, Rosenberg DW, Kester M, Shanmugavelandy SS, Cabot MC. Tamoxifen magnifies therapeutic impact of ceramide in human colorectal cancer cells independent of p53. Biochem Pharmacol 2013; 85:1057-65. [PMID: 23353700 DOI: 10.1016/j.bcp.2013.01.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 01/16/2013] [Accepted: 01/18/2013] [Indexed: 12/28/2022]
Abstract
Poor prognosis in patients with later stage colorectal cancer (CRC) necessitates the search for new treatment strategies. Ceramide, because of its role in orchestrating death cascades in cancer cells, is a versatile alternative. Ceramide can be generated by exposure to chemotherapy or ionizing radiation, or it can be administered in the form of short-chain analogs (C6-ceramide). Because intracellular P-glycoprotein (P-gp) plays a role in catalyzing the conversion of ceramide to higher sphingolipids, we hypothesized that administration of P-gp antagonists with C6-ceramide would magnify cell death cascades. Human CRC cell lines were employed, HCT-15, HT-29, and LoVo. The addition of either tamoxifen, VX-710, verapamil, or cyclosporin A, antagonists of P-gp, enhanced C6-ceramide cytotoxicity in all cell lines. In depth studies with C6-ceramide and tamoxifen in LoVo cells showed the regimen induced PARP cleavage, caspase-dependent apoptosis, mitochondrial membrane permeabilization (MMP), and cell cycle arrest at G1 and G2. At the molecular level, the regimen, but not single agents, induced time-dependent upregulation of tumor suppressor protein p53; however, introduction of a p53 inhibitor staved neither MMP nor apoptosis. Nanoliposomal formulations of C6-ceramide and tamoxifen were also effective, yielding synergistic cell kill. We conclude that tamoxifen is a favorable adjuvant for enhancing C6-ceramide cytotoxicity in CRC, and demonstrates uniquely integrated effects. The high frequency of expression of P-gp in CRC presents an adventitious target for complementing ceramide-based therapies, a strategy that could hold promise for treatment of resistant disease.
Collapse
Affiliation(s)
- Samy A F Morad
- John Wayne Cancer Institute, Santa Monica, CA 90404, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Deguelin induces both apoptosis and autophagy in cultured head and neck squamous cell carcinoma cells. PLoS One 2013; 8:e54736. [PMID: 23372762 PMCID: PMC3553079 DOI: 10.1371/journal.pone.0054736] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 12/14/2012] [Indexed: 12/16/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents more than 5% of all cancers diagnosed annually in United States and around the world. Despite advances in the management of patients with this disease, the survival has not been significantly improved, and the search for potential alternative therapies is encouraging. Here we demonstrate that deguelin administration causes a significant HNSCC cell death. Deguelin induces both cell apoptosis and autophagy by modulating multiple signaling pathways in cultured HNSCC cells. Deguelin inhibits Akt signaling, and down-regulates survivin and cyclin-dependent kinase 4 (Cdk4) expressions, by disrupting their association with heat shock protein-90 (Hsp-90). Deguelin induces ceramide production through de novo synthase pathway to promote HNSCC cell death. Importantly, increased ceramide level activates AMP-activated protein kinase (AMPK), which then directly phosphorylates Ulk1 and eventually leads to cell autophagy. We found that a low dose of deguelin sensitized HNSCC cells to 5-FU. Finally, using a nude mice Hep-2 xenograft model, we also showed a significant anti-tumor ability of deguelin in vivo. Together, we suggest that deguelin may represent a novel and effective chemo-agent against HNSCC.
Collapse
|
|
35
|
Abstract
Sphingolipid-metabolizing enzymes are becoming targets for chemotherapeutic development with an increasing interest in the recent years. In this chapter we introduce the sphingolipid family of lipids, and the role of individual species in cell homeostasis. We also discuss their roles in several rare diseases and overall, in cancer transformation. We follow the biosynthesis pathway of the sphingolipid tree, focusing on the enzymes in order to understand how using small molecule inhibitors makes it possible to modulate cancer progression. Finally, we describe the most used and historically significant inhibitors employed in cancer research, their relationships to sphingolipid metabolism, and some promising results found in this field.
Collapse
Affiliation(s)
- Daniel Canals
- Department of Medicine, University of Stony Brook, Stony Brook, New York 11794
| | - Yusuf A. Hannun
- Health Science Center, Stony Brook University, 100 Nicolls Road, L-4, 178, Stony Brook, NY 11794, USA
| |
Collapse
|
|
36
|
Abstract
Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.
Collapse
|
|
37
|
Abstract
One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of a regulator of cell fate. Ceramide, it turns out, is a powerful tumour suppressor, potentiating signalling events that drive apoptosis, autophagic responses and cell cycle arrest. However, defects in ceramide generation and metabolism in cancer cells contribute to tumour cell survival and resistance to chemotherapy. This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide. The potential of ceramide-based therapeutics in the treatment of cancer is also discussed.
Collapse
Affiliation(s)
- Samy A F Morad
- Department of Experimental Therapeutics, John Wayne Cancer Institute at Saint John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, California 90404, USA.
| | | |
Collapse
|
|
38
|
Brindley DN, Lin FT, Tigyi GJ. Role of the autotaxin-lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy. BIOCHIMICA ET BIOPHYSICA ACTA 2013; 1831:74-85. [PMID: 22954454 PMCID: PMC3584168 DOI: 10.1016/j.bbalip.2012.08.015] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2012] [Revised: 08/20/2012] [Accepted: 08/21/2012] [Indexed: 02/01/2023]
Abstract
High expression of autotaxin in cancers is often associated with increased tumor progression, angiogenesis and metastasis. This is explained mainly since autotaxin produces the lipid growth factor, lysophosphatidate (LPA), which stimulates cell division, survival and migration. It has recently become evident that these signaling effects of LPA also produce resistance to chemotherapy and radiation-induced cell death. This results especially from the stimulation of LPA(2) receptors, which depletes the cell of Siva-1, a pro-apoptotic signaling protein and stimulates prosurvival kinase pathways through a mechanism mediated via TRIP-6. LPA signaling also increases the formation of sphingosine 1-phosphate, a pro-survival lipid. At the same time, LPA decreases the accumulation of ceramides, which are used in radiation therapy and by many chemotherapeutic agents to stimulate apoptosis. The signaling actions of extracellular LPA are terminated by its dephosphorylation by a family of lipid phosphate phosphatases (LPP) that act as ecto-enzymes. In addition, lipid phosphate phoshatase-1 attenuates signaling downstream of the activation of both LPA receptors and receptor tyrosine kinases. This makes many cancer cells hypersensitive to the action of various growth factors since they often express low LPP1/3 activity. Increasing our understanding of the complicated signaling pathways that are used by LPA to stimulate cell survival should identify new therapeutic targets that can be exploited to increase the efficacy of chemo- and radio-therapy. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.
Collapse
Affiliation(s)
- David N Brindley
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
| | | | | |
Collapse
|
|
39
|
Bekele RT, Brindley DN. Role of autotaxin and lysophosphatidate in cancer progression and resistance to chemotherapy and radiotherapy. ACTA ACUST UNITED AC 2012. [DOI: 10.2217/clp.12.30] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
40
|
Ji C, Yang YL, Yang Z, Tu Y, Cheng L, Chen B, Xia JP, Sun WL, Su ZL, He L, Bi ZG. Perifosine sensitizes UVB-induced apoptosis in skin cells: new implication of skin cancer prevention? Cell Signal 2012; 24:1781-9. [PMID: 22584119 DOI: 10.1016/j.cellsig.2012.05.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2012] [Accepted: 05/06/2012] [Indexed: 11/17/2022]
Abstract
We demonstrate here that a relative low dose of perifosine significantly enhanced UVB-induced apoptosis in skin cells (keratinocytes and fibroblasts), associated with a significant increase of reactive oxygen species (ROS) and ceramide production as well as multiple perturbations of diverse cell signaling pathways, shifting to a significant pro-apoptosis outcomes. Perifosine inhibited UVB-induced pro-survival Akt/mammalian target of rapamycin (mTOR) and ERK activation, while facilitating pro-apoptotic AMP-activated protein kinas (AMPK), c-Jun-NH(2)-kinase (JNK), and p53 activation; these signaling changes together promoted a striking increase in skin cell apoptosis and a significantly reduced amount of DNA damages. Our results suggest that perifosine may represent a novel skin cancer prevention strategy.
Collapse
Affiliation(s)
- Chao Ji
- Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu, China.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Korbelik M, Zhang W, Separovic D. Monitoring ceramide and sphingosine-1-phosphate levels in cancer cells and macrophages from tumours treated by photodynamic therapy. Photochem Photobiol Sci 2012; 11:779-84. [PMID: 22354109 DOI: 10.1039/c2pp05384e] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Eradication of tumours by photodynamic therapy (PDT) is accompanied by marked changes in local sphingolipid (SL) engagement. Because of the heterogeneity of cellular composition, analysis of tumour tissue homogenates to quantify SL species is inadequate for evaluating their levels in parenchymal cancer cell population. By staining tumour-derived single cell suspensions with antibodies specific to ceramide and sphingosine 1-phosphate (S1P) followed by flow cytometry, we were able to document changes in the levels of these two key SLs in cancer cells and tumour-associated macrophages (TAMs) of mouse SCCVII tumours following PDT. The results confirm previously obtained indications that tumour treatment by PDT induces a marked rise in ceramide levels in cancer cells within these lesions. Cancer cells from PDT-treated SCCVII tumours undergoing apoptosis were found to have much higher ceramide levels and substantially lower S1P levels than their viable counterparts. Compared to cancer cells, considerably higher ceramide and S1P levels were consistently found in TAMs. Treatment of SCCVII tumour-bearing mice with ceramide analog LCL29 induced a rise in ceramide levels in TAMs but not in cancer cells. When combined with PDT, LCL29 treatment produced a further increase in ceramide levels in TAMs while having no evident impact on ceramide content in cancer cells within same tumours. The results highlight SLs as important participants in tumour response to PDT and potential adjuvant therapeutic targets to PDT.
Collapse
|
|
42
|
Flowers M, Fabriás G, Delgado A, Casas J, Abad JL, Cabot MC. C6-ceramide and targeted inhibition of acid ceramidase induce synergistic decreases in breast cancer cell growth. Breast Cancer Res Treat 2011; 133:447-58. [PMID: 21935601 DOI: 10.1007/s10549-011-1768-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Accepted: 09/02/2011] [Indexed: 01/12/2023]
Abstract
The sphingolipid ceramide is known to play a central role in chemo- and radiation-induced cell death. Acid ceramidase (AC) hydrolyzes ceramide, and thus reduces intracellular levels of this proapoptotic lipid. The role of AC as a putative anticancer target is supported by reports of upregulation in prostate cancer and in some breast tumors. In this study, we determined whether the introduction of an AC inhibitor would enhance the apoptosis-inducing effects of C6-ceramide (C6-cer) in breast cancer cells. Cultured breast cancer cells were treated with DM102 [(2R,3Z)-N-(1-hydroxyoctadec-3-en-2-yl)pivalamide, C6-cer, or the combination. Cell viability and cytotoxic synergy were assessed. Activation of apoptotic pathways, generation of reactive oxygen species, and mitochondrial transmembrane potential were determined. DM102 was a more effective AC inhibitor than N-oleoylethanolamine (NOE) and (1R,2R)-2-N-(tetradecanoylamino)-1-(4'-nitrophenyl)-1,3-propandiol (B-13) in MDA-MB-231, MCF-7, and BT-474 cells. As single agents, C6-cer (IC(50) 5-10 μM) and DM102 (IC(50) 20 μM) were only moderately cytotoxic in MDA-MB-231, MCF-7, and SK-BR-3 cells. Co-administration, however, produced synergistic decreases in viability (combination index <0.5) in all cell lines. Apoptosis was confirmed in MDA-MB-231 cells by detection of caspase 3 cleavage and a >3-fold increase in caspase 3/7 activation, PARP cleavage, and a >70% increase in Annexin-V positive cells. C6-cer/DM102 increased ROS levels 4-fold in MDA-MB-231 cells, shifted the ratio of Bax:Bcl-2 to >9-fold that of control cells, and resulted in mitochondrial membrane depolarization. DM102 also increased the synthesis of (3)H-palmitate-labeled long-chain ceramides by 2-fold when C6-cer was present. These data support the effectiveness of targeting AC in combination with exogenous short-chain ceramide as an anticancer strategy, and warrant continued investigation into the utility of the C6-cer/DM102 drug duo in human breast cancer.
Collapse
Affiliation(s)
- Margaret Flowers
- Department of Experimental Therapeutics, John Wayne Cancer Institute, Santa Monica, CA, USA
| | | | | | | | | | | |
Collapse
|
|
43
|
Tokuda E, Seino Y, Arakawa A, Saito M, Kasumi F, Hayashi SI, Yamaguchi Y. Estrogen receptor-α directly regulates sensitivity to paclitaxel in neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 2011; 133:427-36. [PMID: 21909982 DOI: 10.1007/s10549-011-1758-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Accepted: 08/24/2011] [Indexed: 11/25/2022]
Abstract
Neoadjuvant chemotherapy (NAC) has become the standard treatment for advanced breast cancer. Several prognostic markers, including estrogen receptor-α (ERα), are used to predict the response to NAC. However, the molecular significance of ERα expression in the efficacy of chemotherapy is not yet fully understood. To examine this issue, we first evaluated ERα transcriptional activity in breast cancer cells derived from pre-NAC specimens using estrogen response element-green fluorescent protein (ERE-GFP) as a reporter gene, and found that, in the cases for which ERα activities determined by GFP expression were not detected or low, pCR (pathological complete response) could be achieved even though ERα protein was expressed. Next, we examined the effects of alterations in ERα expression levels on sensitivity to paclitaxel, a key drug in NAC, by stable expression of ERα in ER-negative SKBR3 cells and by siRNA-mediated down-regulation of ERα in ER-positive MCF-7 cells, and showed that ERα expression and sensitivity to paclitaxel showed an inverse correlation. We also established paclitaxel-resistant MCF-7 cell clones and found that they have higher estrogen-induced ER activity than parent cells. Paclitaxel is a microtubule-stabilizing agent, while HDAC6 (histone deacetylase 6), which we previously identified as an estrogen-regulated gene, enhances cell motility by destabilizing microtubules via deacetylation of α-tubulin. Finally, we demonstrate herein that ERα knockdown in MCF-7 cells prevents deacetylation of α-tubulin, thereby increasing sensitivity to paclitaxel. Taken together, these results suggest that ERα expression directly regulates sensitivity to paclitaxel in NAC for breast cancer via the effect on microtubule stability.
Collapse
Affiliation(s)
- Emi Tokuda
- Department of Breast and Endocrine Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Henry B, Möller C, Dimanche-Boitrel MT, Gulbins E, Becker KA. Targeting the ceramide system in cancer. Cancer Lett 2011; 332:286-94. [PMID: 21862212 DOI: 10.1016/j.canlet.2011.07.010] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Revised: 06/30/2011] [Accepted: 07/08/2011] [Indexed: 12/20/2022]
Abstract
Sphingolipids, in particular ceramide, have been described as important components of cellular signalling pathways. Ceramide can be produced via multiple mechanisms including through the hydrolysis of sphingomyelin by acid and neutral sphingomyelinase or by a de novo synthesis pathway. Recent studies have identified sphingomyelinases and ceramide synthases as important targets for γ-irradiation and chemotherapeutic drugs. Likewise, common cancer treatment modalities, such as γ-irradiation and many chemotherapeutic agents, induce cell death via the generation of ceramide. This suggests that the manipulation of ceramide production and metabolism could offer promising means for the enhancement of anti-tumor therapies. The focus of this mini-review will be to discuss contemporary evidence suggesting that ceramide forming pathways and ceramide itself are important targets for the treatment of tumors and the development of novel tumor treatment strategies.
Collapse
Affiliation(s)
- Brian Henry
- Dept. of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45 122 Essen, Germany
| | | | | | | | | |
Collapse
|
|
45
|
Chapman JV, Gouazé-Andersson V, Karimi R, Messner MC, Cabot MC. P-glycoprotein antagonists confer synergistic sensitivity to short-chain ceramide in human multidrug-resistant cancer cells. Exp Cell Res 2011; 317:1736-45. [PMID: 21396934 PMCID: PMC3119367 DOI: 10.1016/j.yexcr.2011.03.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2011] [Revised: 03/02/2011] [Accepted: 03/02/2011] [Indexed: 01/30/2023]
Abstract
P-glycoprotein (P-gp) antagonists inhibit ceramide metabolism at the juncture of glycosylation. The purpose of this study was to test whether targeting P-gp would be a viable alternative to targeting glucosylceramide synthase (GCS) for enhancing ceramide cytotoxicity. A2780 wild-type, and multidrug-resistant 2780AD and NCI/ADR-RES human ovarian cancer cell lines and the cell-permeable ceramide analog, C6-ceramide (C6-cer), were employed. Compared to P-gp-poor A2780 cells, P-gp-rich 2780AD cells converted 3.7-fold more C6-cer to nontoxic C6-glucosylceramide (C6-GC), whereas cell-free GCS activities were equal. 2780AD cells displayed resistance to C6-cer (10 μM) that was reversed by inclusion of the P-gp antagonist tamoxifen (5 μM) but not by inclusion of a GCS inhibitor. Co-administration of C6-cer and P-gp antagonists was also effective in NCI/ADR-RES cells. For example, C6-cer, VX-710 (Biricodar), and cyclosporin A (cyc A) exposure resulted in viabilities of ~90% of control; however, C6-cer/VX-710 and C6-cer/cyc A additions were synergistic and resulted in viabilities of 22% and 17%, respectively. Further, whereas C6-ceramide and cyc A imparted 1.5- and 0-fold increases in caspase 3/7 activity, the combination produced a 3.5-fold increase. Although the upstream elements of cell death have not been elucidated, the novel C6-ceramide/P-gp antagonist combination merits further study and assessment of clinical translational potential.
Collapse
Affiliation(s)
- Jacqueline V. Chapman
- John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California 90404, USA
| | | | - Ramin Karimi
- John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California 90404, USA
| | - Maria C Messner
- John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California 90404, USA
| | - Myles C. Cabot
- John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, California 90404, USA
| |
Collapse
|
|
46
|
Sun H, Yu T, Li J. Co-administration of perifosine with paclitaxel synergistically induces apoptosis in ovarian cancer cells: more than just AKT inhibition. Cancer Lett 2011; 310:118-28. [PMID: 21775054 DOI: 10.1016/j.canlet.2011.06.010] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Revised: 06/09/2011] [Accepted: 06/12/2011] [Indexed: 12/28/2022]
Abstract
Here we report an oral alkylphospholipid perifosine dramatically sensitizes chemo-resistant ovarian cancer cells to paclitaxel induced cell death and apoptosis in vitro. We found that co-administration perifosine with paclitaxel in human ovarian cancer cells led to the inhibition of AKT/mTOR complex 1 (mTORC1), a marked increase in ceramide and reactive oxygen species (ROS) production, and a striking increase in the activation of pro-apoptosis pathways, including caspase 3, c-Jun N-terminal kinases (JNK) and AMP-activated protein kinase (AMPK). These signaling events together caused a marked increase of cancer cell apoptosis. Combining paclitaxel with perifosine may represent a novel anti-ovarian cancer strategy.
Collapse
Affiliation(s)
- Hui Sun
- Central Lab., Jining First People's Hospital, 6 Jiankang Road, Jining City, Shandong Province 272111, PR China
| | | | | |
Collapse
|
|
47
|
Samadi N, Bekele RT, Goping IS, Schang LM, Brindley DN. Lysophosphatidate induces chemo-resistance by releasing breast cancer cells from taxol-induced mitotic arrest. PLoS One 2011; 6:e20608. [PMID: 21647386 PMCID: PMC3103588 DOI: 10.1371/journal.pone.0020608] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2011] [Accepted: 05/05/2011] [Indexed: 11/18/2022] Open
Abstract
Background Taxol is a microtubule stabilizing agent that arrests cells in mitosis leading to cell death. Taxol is widely used to treat breast cancer, but resistance occurs in 25–69% of patients and it is vital to understand how Taxol resistance develops to improve chemotherapy. The effects of chemotherapeutic agents are overcome by survival signals that cancer cells receive. We focused our studies on autotaxin, which is a secreted protein that increases tumor growth, aggressiveness, angiogenesis and metastasis. We discovered that autotaxin strongly antagonizes the Taxol-induced killing of breast cancer and melanoma cells by converting the abundant extra-cellular lipid, lysophosphatidylcholine, into lysophosphatidate. This lipid stimulates specific G-protein coupled receptors that activate survival signals. Methodology/Principal Findings In this study we determined the basis of these antagonistic actions of lysophosphatidate towards Taxol-induced G2/M arrest and cell death using cultured breast cancer cells. Lysophosphatidate does not antagonize Taxol action in MCF-7 cells by increasing Taxol metabolism or its expulsion through multi-drug resistance transporters. Lysophosphatidate does not lower the percentage of cells accumulating in G2/M by decreasing exit from S-phase or selective stimulation of cell death in G2/M. Instead, LPA had an unexpected and remarkable action in enabling MCF-7 and MDA-MB-468 cells, which had been arrested in G2/M by Taxol, to normalize spindle structure and divide, thus avoiding cell death. This action involves displacement of Taxol from the tubulin polymer fraction, which based on inhibitor studies, depends on activation of LPA receptors and phosphatidylinositol 3-kinase. Conclusions/Significance This work demonstrates a previously unknown consequence of lysophosphatidate action that explains why autotaxin and lysophosphatidate protect against Taxol-induced cell death and promote resistance to the action of this important therapeutic agent.
Collapse
Affiliation(s)
- Nasser Samadi
- Department of Biochemistry (Signal Transduction Research Group), School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Raie T. Bekele
- Department of Biochemistry (Signal Transduction Research Group), School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ing Swie Goping
- Department of Biochemistry (Signal Transduction Research Group), School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Luis M. Schang
- Department of Biochemistry (Signal Transduction Research Group), School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - David N. Brindley
- Department of Biochemistry (Signal Transduction Research Group), School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada
- * E-mail:
| |
Collapse
|
|
48
|
Beuster G, Zarse K, Kaleta C, Thierbach R, Kiehntopf M, Steinberg P, Schuster S, Ristow M. Inhibition of alanine aminotransferase in silico and in vivo promotes mitochondrial metabolism to impair malignant growth. J Biol Chem 2011; 286:22323-30. [PMID: 21540181 PMCID: PMC3121379 DOI: 10.1074/jbc.m110.205229] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Cancer cells commonly exhibit increased nonoxidative d-glucose metabolism whereas induction of mitochondrial metabolism may impair malignant growth. We have first used an in silico method called elementary mode analysis to identify inhibition of ALAT (l-alanine aminotransferase) as a putative target to promote mitochondrial metabolism. We then experimentally show that two competitive inhibitors of ALAT, l-cycloserine and β-chloro-l-alanine, inhibit l-alanine production and impair d-glucose uptake of LLC1 Lewis lung carcinoma cells. The latter inhibition is linked to an initial energy deficit, as quantified by decreased ATP content, which is then followed by an activation of AMP-activated protein kinase and subsequently increased respiration rates and mitochondrial production of reactive oxygen species, culminating in ATP replenishment in ALAT-inhibited LLC1 cells. Moreover, we observe altered phosphorylation of p38 MAPK (mitogen-activated protein kinase 14), ERK (extracellular signal-regulated kinase 1/2), and Rb1 (retinoblastoma 1) proteins, as well as decreased expression of Cdc25a (cell decision cycle 25 homolog A) and Cdk4 (cyclin-dependent kinase 4). Importantly, these sequelae of ALAT inhibition culminate in similarly reduced anchorage-dependent and anchorage-independent growth rates of LLC1 cells, together suggesting that inhibition of ALAT efficiently impairs cancer growth by counteracting the Warburg effect due to compensatory activation of mitochondrial metabolism.
Collapse
Affiliation(s)
- Gregor Beuster
- Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena D-07743, Germany
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
C16-Ceramide Analog Combined with Pc 4 Photodynamic Therapy Evokes Enhanced Total Ceramide Accumulation, Promotion of DEVDase Activation in the Absence of Apoptosis, and Augmented Overall Cell Killing. J Lipids 2010; 2011:713867. [PMID: 21490809 PMCID: PMC3066794 DOI: 10.1155/2011/713867] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Accepted: 09/24/2010] [Indexed: 12/13/2022] Open
Abstract
Because of the failure of single modality approaches, combination therapy for cancer treatment is a promising alternative. Sphingolipid analogs, with or without anticancer drugs, can improve tumor response. C16-pyridinium ceramide analog LCL30, was used in combination with photodynamic therapy (PDT), an anticancer treatment modality, to test the hypothesis that the combined treatment will trigger changes in the sphingolipid profile and promote cell death. Using SCCVII mouse squamous carcinoma cells, and the silicone phthalocyanine Pc 4 for PDT, we showed that combining PDT with LCL30 (PDT/LCL30) was more effective than individual treatments in raising global ceramide levels, as well as in reducing dihydrosphingosine levels. Unlike LCL30, PDT, alone or combined, increased total dihydroceramide levels. Sphingosine levels were unaffected by LCL30, but were abolished after PDT or the combination. LCL30-triggered rise in sphingosine-1-phosphate was reversed post-PDT or the combination. DEVDase activation was evoked after PDT or LCL30, and was promoted post- PDT/LCL30. Neither mitochondrial depolarization nor apoptosis were observed after any of the treatments. Notably, treatment with the combination resulted in augmented overall cell killing. Our data demonstrate that treatment with PDT/LCL30 leads to enhanced global ceramide levels and DEVDase activation in the absence of apoptosis, and promotion of total cell killing.
Collapse
|
|
50
|
Separovic D, Bielawski J, Pierce JS, Merchant S, Tarca AL, Bhatti G, Ogretmen B, Korbelik M. Enhanced tumor cures after Foscan photodynamic therapy combined with the ceramide analog LCL29. Evidence from mouse squamous cell carcinomas for sphingolipids as biomarkers of treatment response. Int J Oncol 2010; 38:521-7. [PMID: 21152858 DOI: 10.3892/ijo.2010.863] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Accepted: 08/02/2010] [Indexed: 01/12/2023] Open
Abstract
To improve anticancer therapeutic success of photodynamic therapy (PDT), combination treatments represent a viable strategy. Sphingolipid analogs combined with anticancer drugs can enhance tumor response. We have shown that LCL29, a C6-pyridinium ceramide, promotes therapeutic efficacy of Photofrin-PDT in mouse SCCVII squamous cell carcinoma tumors. The long-term effect of the combination PDT + LCL29 is unknown. In this study we used the same model to test the long-term curative potential of Foscan-PDT + LCL29. We show that treatment of SCCVII tumors with the combination led to enhanced long-term tumor cure compared to PDT alone. LCL29 itself did not prevent tumor growth. All treatments triggered early increases in tumor-associated C16-ceramide, C18-ceramide, dihydrosphingosine, and global levels of dihydroceramides. PDT-evoked increases in tumor-associated sphingosine-1-phosphate and dihydrosphingosine-1-phosphate remained elevated or were attenuated after the combination, respectively; in contrast, LCL29 had no effect on these two sphingolipids. Our data demonstrate that adjuvant LCL29 improves PDT long-term therapeutic efficacy, implying translational potential of the combination. Furthermore, our findings indicate that changes in the sphingolipid profile might serve as predictive biomarkers of tumor response to treatments.
Collapse
Affiliation(s)
- D Separovic
- Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Ave, Detroit, MI 48201, USA.
| | | | | | | | | | | | | | | |
Collapse
|