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Xu M, Zhou J, Lv J, Zhang Y. Tumor suppressing function of SLC16A7 in bladder cancer and its pan-cancer analysis. BMC Cancer 2025; 25:932. [PMID: 40410718 PMCID: PMC12102997 DOI: 10.1186/s12885-025-14345-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 05/16/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND Bladder cancer (BCa), a prevalent malignancy of the urinary tract, is associated with high recurrence and mortality rates. SLC16A7, a member of the solute carrier family 16 (SLC16), encodes monocarboxylate transporters that are involved in the proton-coupled transport of metabolites, including lactate, pyruvate, and ketone bodies, across cell membranes. Evidence suggests that SLC16A7 exhibits variable expression in cancers and may influence tumor development, progression, and immune regulation. This study examined the role of SLC16A7 in cancer prognosis, progression, and immune regulation, focusing on BCa. METHODS A comprehensive analysis was conducted to evaluate the clinical and immunological relevance of SLC16A7 across multiple cancer types using data from 33 tumor datasets from 'The Cancer Genome Atlas (TCGA). ' Associations between SLC16A7 expression and clinicopathological features, prognostic indicators, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and immune-related gene expression were systematically analyzed. Experimental validation was performed to assess SLC16A7 expression in the BCa tissues and cell lines. The prognostic value of SLC16A7 was confirmed using clinical follow-up data from an independent patient cohort. Functional studies included proliferation assays to investigate the effect of SLC16A7. CD8 + T cells were obtained from the peripheral blood of healthy donors and stimulated using CD3 and CD28 antibodies in combination with recombinant IL-2. To investigate the immunological role of SLC16A7, co-culture experiments were performed between BCa cells and activated CD8 + T cells. Additionally, CD8 + T cell chemotaxis assays and ELISA analyses were conducted to evaluate the immune responses mediated by SLC16A7. RESULTS SLC16A7 expression was downregulated in 16 cancer types, including BCa, and upregulated in three cancer types. Its expression was significantly associated with tumor stage in four cancers and showed both positive and negative correlations with prognosis, depending on the cancer type. Genomic analyses revealed significant associations between SLC16A7 and TMB in 13 cancer types and MSI in 11 cancer types. Pathway enrichment analyses (Hallmark-GSEA and KEGG-GSEA) indicated strong associations between SLC16A7, immune responses, and tumor progression. Immune infiltration analysis showed a predominantly positive association between SLC16A7 expression and immune cell infiltration, except in low-grade gliomas (LGG). CIBERSORT analysis demonstrated that SLC16A7 expression correlated positively with resting memory CD4 T cells, eosinophils, monocytes, resting mast cells, and memory B cells and negatively with activated memory CD4 T cells, M1 macrophages, follicular helper T cells, M0 macrophages, and CD8 T cells. SLC16A7 expression was also significantly associated with the expression of immune-regulatory molecules. Experimental validation showed reduced SLC16A7 expression in BCa tissues and cell lines compared to that in their normal counterparts. Kaplan-Meier survival analysis indicated that higher SLC16A7 expression was correlated with better overall survival in patients with BCa. Functional assays revealed that SLC16A7 inhibited BCa cell progression and promoted the chemotaxis and tumor-killing ability of CD8 + T cells in the BCa tumor microenvironment (TME). CONCLUSIONS SLC16A7 exhibits tumor-suppressive properties, with downregulation in most cancers, and is associated with favorable prognosis and enhanced immune responses. SLC16A7 functions as a tumor suppressor in BCa and is associated with improved survival outcomes. These findings suggest that SLC16A7 is a potential biomarker for cancer diagnosis and prognosis.
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Affiliation(s)
- Mingjie Xu
- Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiatong Zhou
- Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiancheng Lv
- Department of Urology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Yu Zhang
- Department of Urology, Xiangshan Hospital of Wenzhou Medical University, Ningbo, Zhejiang, China.
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Ghimire K, Awasthi BP, Yadav K, Lee J, Kim H, Jeong BS, Kim JA. Prostate cancer-selective anticancer action of an oxindole derivative via HO-1-mediated disruption of metabolic reprogramming. Chem Biol Interact 2025; 408:111393. [PMID: 39842705 DOI: 10.1016/j.cbi.2025.111393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/26/2024] [Accepted: 01/20/2025] [Indexed: 01/24/2025]
Abstract
Prostate cancer, the second leading cause of cancer-related mortality in men, exhibits distinct metabolic reprogramming involving zinc and citrate metabolism. This study investigated whether targeting this unique metabolic profile could offer an effective therapeutic approach. A series of novel oxindole derivatives were synthesized and evaluated for their inhibitory effects on transcription factors (TFs) and antiproliferative activity across various cancer cell lines. Among these, compound 3D showed the strongest inhibition of master TFs (HIF-1α, c-Myc, and SP-1) and demonstrated selective antiproliferative activity in prostate cancer cells. In PC-3 and LNCaP cells, compound 3D suppressed aerobic glycolysis by downregulating lactate-modulating genes (LDHA, MCT1/4, and CAIX) and the zinc influx transporter (ZIP1), without affecting the zinc efflux transporter (ZnT4). Notably, 3D selectively increased heme oxygenase-1 (HO-1) levels in prostate cancer cells, as shown by the proteome profiler oncogene array assay and confirmed by Western blotting. This response was reversed by ZnCl2 treatment. The decreases in LDHA, mitochondrial mass (measured by FACS), and cell proliferation induced by compound 3D were blocked by HO-1-IN-1, an HO-1 inhibitor, and ZnCl2. Furthermore, 3D induced a more pronounced reduction in the oxygen consumption rate (OCR) than in the extracellular acidification rate (EACR), indicating a strong effect on oxidative metabolism. 3D exhibited dose-dependent antitumour efficacy in vivo comparable to that of docetaxel. These findings reveal that the oxindole derivative 3D substantially lowers intracellular zinc levels, yielding potent antitumour effects in prostate cancer through HO-1 upregulation, which impairs mitochondrial function more significantly than aerobic glycolysis.
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Affiliation(s)
- Kalpana Ghimire
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | | | - Kiran Yadav
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Jiwoo Lee
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Hyunjin Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea
| | - Byeong-Seon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
| | - Jung-Ae Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, 38541, Republic of Korea.
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Jardin C, Derst C, Franzen A, Mahorivska I, DeCoursey TE, Musset B, Chaves G. Biophysical Properties of Somatic Cancer Mutations in the S4 Transmembrane Segment of the Human Voltage-Gated Proton Channel hH V1. Biomolecules 2025; 15:156. [PMID: 40001460 PMCID: PMC11853527 DOI: 10.3390/biom15020156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 02/27/2025] Open
Abstract
Somatic mutations are common in cancer, with only a few driving the progression of the disease, while most are silent passengers. Some mutations may hinder or even reverse cancer progression. The voltage-gated proton channel (HV1) plays a key role in cellular pH homeostasis and shows increased expression in several malignancies. Inhibiting HV1 in cancer cells reduces invasion, migration, proton extrusion, and pH recovery, impacting tumor progression. Focusing on HVCN1, the gene coding for the human voltage-gated proton channel (hHV1), 197 mutations were identified from three databases: 134 missense mutations, 51 sense mutations, and 12 introducing stop codons. These mutations cluster in two hotspots: the central region of the N-terminus and the region coding for the S4 transmembrane domain, which contains the channel's voltage sensor. Five somatic mutations within the S4 segment (R205W, R208W, R208Q, G215E, and G215R) were selected for electrophysiological analysis and MD simulations. The findings reveal that while all mutants remain proton-selective, they all exhibit reduced effective charge displacement and proton conduction. The mutations differentially affect hHV1 kinetics, with the most pronounced effects observed in the two Arg-to-Trp substitutions. Mutation of the first voltage-sensing arginine (R1) to tryptophan (R205W) causes proton leakage in the closed state, accelerates channel activation, and diminishes the voltage dependence of gating. Except for R205W, the mutations promote the deactivated channel configuration. Altogether, these data are consistent with impairment of hHV1 function by mutations in the S4 transmembrane segment, potentially affecting pH homeostasis of tumor cells.
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Affiliation(s)
- Christophe Jardin
- Center of Physiology, Pathophysiology and Biophysics-Nuremberg, Paracelsus Medical University, 90419 Nuremberg, Germany; (C.J.); (C.D.); (I.M.); (B.M.)
| | - Christian Derst
- Center of Physiology, Pathophysiology and Biophysics-Nuremberg, Paracelsus Medical University, 90419 Nuremberg, Germany; (C.J.); (C.D.); (I.M.); (B.M.)
| | - Arne Franzen
- Institut für Biologische Informationsprozesse, Molekular-und Zellphysiologie (IBI-1), Forschungszentrum Jülich, 52428 Jülich, Germany;
| | - Iryna Mahorivska
- Center of Physiology, Pathophysiology and Biophysics-Nuremberg, Paracelsus Medical University, 90419 Nuremberg, Germany; (C.J.); (C.D.); (I.M.); (B.M.)
| | - Thomas E. DeCoursey
- Department of Physiology & Biophysics, Rush University, Chicago, IL 60612, USA;
| | - Boris Musset
- Center of Physiology, Pathophysiology and Biophysics-Nuremberg, Paracelsus Medical University, 90419 Nuremberg, Germany; (C.J.); (C.D.); (I.M.); (B.M.)
| | - Gustavo Chaves
- Center of Physiology, Pathophysiology and Biophysics-Nuremberg, Paracelsus Medical University, 90419 Nuremberg, Germany; (C.J.); (C.D.); (I.M.); (B.M.)
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Suliman S, Ellaithi M. Immunohistochemical Detection of CD147 Expression in Adenocarcinoma of the Prostate: A Case-Control Study. Prostate Cancer 2024; 2024:4406057. [PMID: 39735939 PMCID: PMC11682863 DOI: 10.1155/proc/4406057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 11/22/2024] [Indexed: 12/31/2024] Open
Abstract
Prostate cancer is the most common noncutaneous malignancy among men worldwide, including in Sudan, where it represents a significant public health challenge. CD147, a transmembrane glycoprotein implicated in tumor progression, invasion, and metastasis, has shown potential as a prognostic biomarker in various cancers. This retrospective case-control study aimed to evaluate CD147 expression in prostate adenocarcinoma among Sudanese men and its association with tumor grade. A total of 80 paraffin-embedded tissue samples, including 40 cases of prostate adenocarcinoma and 40 benign prostatic hyperplasia (BPH) controls, were analyzed using immunohistochemistry. CD147 expression was observed in 22.5% of adenocarcinoma cases compared to 7% of controls; however, the association was not statistically significant (p=0.07). Low-grade tumors were predominant in the cohort, consistent with early-stage diagnoses. The findings revealed no clear link between CD147 expression and tumor grade, diverging from prior studies that associate CD147 with advanced tumor stages. The nonsignificant results may be attributed to the small sample size, emphasizing the need for future research with larger, more diverse cohorts, advanced molecular techniques, and functional studies to better elucidate the role of CD147 in prostate cancer pathogenesis and its potential as a therapeutic target.
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Affiliation(s)
- Sara Suliman
- Department of Histopathology and Cytology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan
| | - Mona Ellaithi
- Department of Histopathology and Cytology, Faculty of Medical Laboratory Sciences, Al-Neelain University, Khartoum, Sudan
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5
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Gao C, Yang B, Li Y, Pei W. Monocarboxylate transporter dependent mechanism is involved in proliferation, migration, and invasion of human glioblastoma cell lines via activation of PI3K/Akt signaling pathway. PLoS One 2024; 19:e0312939. [PMID: 39475905 PMCID: PMC11524508 DOI: 10.1371/journal.pone.0312939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 10/15/2024] [Indexed: 11/02/2024] Open
Abstract
Glioblastoma multiforme is one of the most common primary tumors of the central nervous system, with a very poor prognosis. Cancer cells have been observed to upregulate pH regulators, such as monocarboxylate transporters (MCTs), with an increase in MCT4 expression being observed in several malignancies. MCT4/ recombinant cluster of differentiation 147 (CD147) transporter complex was reported to stimulate vascular endothelial growth factor (VEGF) via the phosphatidylinositol 3 kinase (PI3K) /protein kinase B (Akt) pathway, which has been proven to mediate glioblastoma invasion and migration. The present study aimed to clarify the role of the MCT4/CD147 transporter complex in glioblastoma cell proliferation, migration, and invasion. In this work, lentiviral vectors were used to overexpress MCT4/CD147 and small interfering RNA (siRNA) was used to silence MCT4/CD147 in the human glioma cell lines U87 and U251, respectively. The effects on cell proliferation, migration and invasiveness, as well as the protein expression levels of MCT4 and CD147, extracellular lactate content and Akt activation were assessed by MTT, wound-healing and invasion assays, western blotting and colorimetric method, respectively. The analysis results suggested that cell proliferation, migration, invasion, and Akt activation were decreased by siRNA in all cell lines, but were increased by lentivirus-mediated MCT4 overexpression. These findings suggest that inhibiting the activity and expression of the MCT4/CD147 transporter complex via metabolic-targeting drugs, particularly in cells with a high rate of glycolysis, should be explored as a novel strategy for glioblastoma treatment.
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Affiliation(s)
- Chen Gao
- Department of General Practice, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| | - Binni Yang
- Department of General Practice, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| | - Yurong Li
- Department of General Practice, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
| | - Wenjuan Pei
- Department of General Practice, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou, China
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Sushentsev N, Hamm G, Flint L, Birtles D, Zakirov A, Richings J, Ling S, Tan JY, McLean MA, Ayyappan V, Horvat Menih I, Brodie C, Miller JL, Mills IG, Gnanapragasam VJ, Warren AY, Barry ST, Goodwin RJA, Barrett T, Gallagher FA. Metabolic imaging across scales reveals distinct prostate cancer phenotypes. Nat Commun 2024; 15:5980. [PMID: 39013948 PMCID: PMC11252279 DOI: 10.1038/s41467-024-50362-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Accepted: 07/07/2024] [Indexed: 07/18/2024] Open
Abstract
Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.
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Affiliation(s)
- Nikita Sushentsev
- Department of Radiology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
| | - Gregory Hamm
- Integrated BioAnalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Lucy Flint
- Integrated BioAnalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Daniel Birtles
- Integrated BioAnalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Aleksandr Zakirov
- Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Jack Richings
- Predictive AI & Data, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Stephanie Ling
- Integrated BioAnalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Jennifer Y Tan
- Predictive AI & Data, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Mary A McLean
- Department of Radiology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Vinay Ayyappan
- Department of Radiology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Ines Horvat Menih
- Department of Radiology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Cara Brodie
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Jodi L Miller
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Ian G Mills
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Vincent J Gnanapragasam
- Department of Urology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Division of Urology, Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Urology Translational Research and Clinical Trials Office, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK
| | - Anne Y Warren
- Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Simon T Barry
- Bioscience, Early Oncology, AstraZeneca, Cambridge, UK
| | - Richard J A Goodwin
- Integrated BioAnalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK
| | - Tristan Barrett
- Department of Radiology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Ferdia A Gallagher
- Department of Radiology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Koltai T, Fliegel L. Exploring monocarboxylate transporter inhibition for cancer treatment. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:135-169. [PMID: 38464385 PMCID: PMC10918235 DOI: 10.37349/etat.2024.00210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/01/2023] [Indexed: 03/12/2024] Open
Abstract
Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.
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Affiliation(s)
- Tomas Koltai
- Hospital del Centro Gallego de Buenos Aires, Buenos Aires 2199, Argentina
| | - Larry Fliegel
- Department of Biochemistry, Faculty of Medicine, University of Alberta, Edmonton T6G 2R3, Alberta, Canada
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Vovdenko S, Morozov A, Ali S, Kogan E, Bezrukov E. Role of monocarboxylate transporters and glucose transporters in prostate cancer. Urologia 2023; 90:491-498. [PMID: 35903832 DOI: 10.1177/03915603221111125] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
OBJECTIVES Currently, research of new diagnostic approaches to detect clinically significant prostate cancer is relevant because of the importance of early detection of aggressive forms of the disease, often challenging, even when using modern diagnostic tools. The aim of this review is to present the current knowledge regarding monocarboxylate transporters' and glucose transporters' expression as a component of glycolytic phenotype definition in prostate cancer cells. METHODS We searched PubMed and Scopus databases. Twenty-six articles from 2003 to 2022 were included. Literature research and selection were carried out based on the recommendations of the PRISMA statement. RESULTS The presence of "lactate shuttle" in the tumor tissue is associated with a worse prognosis. Increased expression of MCT2, MCT4, GLUT1, and down-regulation of GLUT3 are associated with prostate adenocarcinoma. MCT4 expression level correlates with the grade of tumor malignancy and disease prognosis. Up-regulation of GLUT1 and MCT4 is typical for hormone-resistant prostate cancer. Inhibition of MCT1 and MCT4 and GLUT1 in prostate cancer cells reduces their metabolic activity and growth rate, a suitable novel approach for targeted therapy. CONCLUSION Review of the current studies showed that expression of certain MCTs and GLUTs types are associated with prostate cancer and some of them correlate with high malignancy and poor prognosis. Detection by immunohistochemistry of these transporters could represent a new diagnostic tool to identify aggressive forms of prostate cancer, and a novel therapeutic target for selective drugs.
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Affiliation(s)
- Stanislav Vovdenko
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Andrey Morozov
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Stanislav Ali
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Evgeniia Kogan
- A.I. Strukov Department of Pathological Anatomy, Sechenov University, Moscow, Russia
| | - Evgeny Bezrukov
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
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Chetta P, Sriram R, Zadra G. Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications? Cancers (Basel) 2023; 15:3473. [PMID: 37444583 PMCID: PMC10340474 DOI: 10.3390/cancers15133473] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/24/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Advanced prostate cancer represents the fifth leading cause of cancer death in men worldwide. Although androgen-receptor signaling is the major driver of the disease, evidence is accumulating that disease progression is supported by substantial metabolic changes. Alterations in de novo lipogenesis and fatty acid catabolism are consistently reported during prostate cancer development and progression in association with androgen-receptor signaling. Therefore, the term "lipogenic phenotype" is frequently used to describe the complex metabolic rewiring that occurs in prostate cancer. However, a new scenario has emerged in which lactate may play a major role. Alterations in oncogenes/tumor suppressors, androgen signaling, hypoxic conditions, and cells in the tumor microenvironment can promote aerobic glycolysis in prostate cancer cells and the release of lactate in the tumor microenvironment, favoring immune evasion and metastasis. As prostate cancer is composed of metabolically heterogenous cells, glycolytic prostate cancer cells or cancer-associated fibroblasts can also secrete lactate and create "symbiotic" interactions with oxidative prostate cancer cells via lactate shuttling to sustain disease progression. Here, we discuss the multifaceted role of lactate in prostate cancer progression, taking into account the influence of the systemic metabolic and gut microbiota. We call special attention to the clinical opportunities of imaging lactate accumulation for patient stratification and targeting lactate metabolism.
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Affiliation(s)
- Paolo Chetta
- Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA;
| | - Renuka Sriram
- Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94143, USA;
| | - Giorgia Zadra
- Institute of Molecular Genetics, National Research Council (IGM-CNR), 27100 Pavia, Italy
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Liu X, Qin H, Zhang L, Jia C, Chao Z, Qin X, Zhang H, Chen C. Hyperoxia induces glucose metabolism reprogramming and intracellular acidification by suppressing MYC/MCT1 axis in lung cancer. Redox Biol 2023; 61:102647. [PMID: 36867943 PMCID: PMC10011425 DOI: 10.1016/j.redox.2023.102647] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
The perils and promises of inspiratory hyperoxia (IH) in oncology are still controversial, especially for patients with lung cancer. Increasing evidence shows that hyperoxia exposure is relevant to the tumor microenvironment. However, the detailed role of IH on the acid-base homeostasis of lung cancer cells remains unclear. In this study, the effects of 60% oxygen exposure on intra- and extracellular pH were systematically evaluated in H1299 and A549 cells. Our data indicate that hyperoxia exposure reduces intracellular pH, which might be expected to reduce the proliferation, invasion, and epithelial-to-mesenchymal transition of lung cancer cells. RNA sequencing, Western blot, and PCR analysis reveal that monocarboxylate transporter 1 (MCT1) mediates intracellular lactate accumulation and intracellular acidification of H1299 and A549 cells at 60% oxygen exposure. In vivo studies further demonstrate that MCT1 knockdown dramatically reduces lung cancer growth, invasion, and metastasis. The results of luciferase and ChIP-qPCR assays further confirm that MYC is a transcription factor of MCT1, and PCR and Western blot assays confirm that MYC is downregulated under hyperoxic conditions. Collectively, our data reveal that hyperoxia can suppress the MYC/MCT1 axis and cause the accumulation of lactate and intracellular acidification, thereby retarding tumor growth and metastasis.
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Affiliation(s)
- Xiucheng Liu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China; Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China
| | - Hao Qin
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China; Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, China
| | - Li Zhang
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China
| | - Caili Jia
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China
| | - Zhixiang Chao
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China
| | - Xichun Qin
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China
| | - Hao Zhang
- Thoracic Surgery Laboratory, Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China; Department of Thoracic Surgery, Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221006, Jiangsu, China.
| | - Chang Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China; Shanghai Engineering Research Center of Lung Transplantation, Shanghai, China.
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11
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Zhang H, Wang Z, Gao T, Wang Z, Ren C, Liu J. An enzyme-instructed self-assembly system induces tumor acidosis via sequential-dual effect for cancer selective therapy. Acta Biomater 2023; 164:447-457. [PMID: 36996995 DOI: 10.1016/j.actbio.2023.03.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/06/2023] [Accepted: 03/23/2023] [Indexed: 03/31/2023]
Abstract
The acidosis anti-tumor therapy, based on the altered energy metabolism pathway of tumor cells, has been proposed as an attractive method for cancer selective treatment. However, the strategy of inducing tumor acidosis by using a single drug to simultaneously inhibit both lactate efflux and consumption has not been reported yet. Herein, an in situ enzyme-instructed self-assembly (EISA) system was rationally fabricated to induce tumor acidosis apoptosis for cancer selective therapy. Depending on the sequential effect of the in situ EISA system, the targeted drug was successively distributed on the membrane and intracellular, inhibiting MCT4 mediated lactate efflux and mitochondrial tricarboxylic acid (TCA) cycle mediated lactate consumption, respectively. Through the dual obstruction of lactate metabolism to trigger tumor acidosis, the in situ EISA nanomedicine showed selective growth and migration inhibition against cancer cells. In addition, the nanomedicine also displayed a radio-sensitization effect in vitro due to causing the mitochondrial dysfunction, and exhibited a prominent synergistic chemo-radiotherapy anti-tumor performance in vivo. Accordingly, this work demonstrated that the in situ EISA system could endow the LND with sequential-dual effects to induce tumor acidosis, which may provide an enlightening strategy for anticancer drug delivery and cancer selective therapy. STATEMENT OF SIGNIFICANCE: With the help of the sequential effect of in situ EISA, the serial attack of LND against different targets was effectively realized to induce tumor acidosis and combined chemo-radiotherapy, implying the importance of the relationship between structure and function, which could offer a distinctive inspiration for future drug delivery system design and anti-tumor application.
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12
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Nwosu ZC, Song MG, di Magliano MP, Lyssiotis CA, Kim SE. Nutrient transporters: connecting cancer metabolism to therapeutic opportunities. Oncogene 2023; 42:711-724. [PMID: 36739364 PMCID: PMC10266237 DOI: 10.1038/s41388-023-02593-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 02/05/2023]
Abstract
Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.
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Affiliation(s)
- Zeribe Chike Nwosu
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
| | - Mun Gu Song
- Department of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea
- Department of Integrated Biomedical and Life Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea
| | | | - Costas A Lyssiotis
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
| | - Sung Eun Kim
- Department of Biosystems and Biomedical Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea.
- Department of Integrated Biomedical and Life Sciences, College of Health Sciences, Korea University, Seoul, 02841, Republic of Korea.
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13
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Zhao H, Chen Y, Liao YP, Chen HM, Yang QH, Xiao Y, Luo J, Chen ZZ, Yi L, Hu GY. Immunohistochemical evaluation and prognostic value of monocarboxylate transporter 1 (MCT1) and 4 (MCT4) in T-cell non-Hodgkin lymphoma. Clin Exp Med 2023; 23:55-64. [PMID: 35239073 DOI: 10.1007/s10238-022-00805-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 02/05/2022] [Indexed: 01/17/2023]
Abstract
Tumor cells often exhibit the Warburg effect, wherein, they preferentially undergo glycolysis over oxidative phosphorylation for energy production. Monocarboxylate transporter 1 (MCT1) and 4 (MCT4) are critical symporters mediating lactate efflux and preventing intracellular acidification during tumor growth. Numerous studies have focused on inhibiting MCT1 or MCT4 in various cancers. However, its role in T-cell lymphoma (TCL) is not yet investigated owing to the low incidence of TCL. This study was designed to investigate the expression of MCT1/MCT4 in patients with TCL and determine their prognostic value in this cancer. We performed immunohistochemistry to evaluate the expression level of MCT1/MCT4 in 38 TCL tissue samples and then compared their expression among different TCL subgroups, which were formed based on different clinical characteristics. Survival analysis was performed to evaluate the relationship between MCT1/MCT4 expression and both overall survival (OS) and progression-free survival (PFS). Our results revealed that MCT1 and MCT4 expression was significantly increased in TCL tissues compared to the control group. In addition, increased MCT1 expression associated with the female sex, advanced disease stage, increased serum LDH, Ki-67 at ≥ 50%, and intermediate or high-risk groups as categorized by the International Prognostic Index (IPI) score. We also found that increased MCT1 expression may be associated with reduced OS and PFS. In conclusion, MCT1 and MCT4 are overexpressed in patients with TCL and may predict poor prognosis. MCT1 inhibition might be a novel treatment strategy for TCL, and further preclinical trials are required.
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Affiliation(s)
- Hu Zhao
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Yuan Chen
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - You-Ping Liao
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Hai-Mei Chen
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Qiu-Hong Yang
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Yin Xiao
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Jing Luo
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Zhen-Zhen Chen
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Lai Yi
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China
| | - Guo-Yu Hu
- XiangYa School of Medicine, Department of Hematology, Central South University, The Affiliated Zhuzhou Hospital, No.116 Changjiang South Road, Tianyuan District, Zhuzhou, Hunan, China.
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14
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Puris E, Fricker G, Gynther M. The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy. Pharmaceutics 2023; 15:pharmaceutics15020364. [PMID: 36839686 PMCID: PMC9966068 DOI: 10.3390/pharmaceutics15020364] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells.
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15
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Alvear-Arias JJ, Pena-Pichicoi A, Carrillo C, Fernandez M, Gonzalez T, Garate JA, Gonzalez C. Role of voltage-gated proton channel (Hv1) in cancer biology. Front Pharmacol 2023; 14:1175702. [PMID: 37153807 PMCID: PMC10157179 DOI: 10.3389/fphar.2023.1175702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/11/2023] [Indexed: 05/10/2023] Open
Abstract
The acid-base characteristics of tumor cells and the other elements that compose the tumor microenvironment have been topics of scientific interest in oncological research. There is much evidence confirming that pH conditions are maintained by changes in the patterns of expression of certain proton transporters. In the past decade, the voltage-gated proton channel (Hv1) has been added to this list and is increasingly being recognized as a target with onco-therapeutic potential. The Hv1 channel is key to proton extrusion for maintaining a balanced cytosolic pH. This protein-channel is expressed in a myriad of tissues and cell lineages whose functions vary from producing bioluminescence in dinoflagellates to alkalizing spermatozoa cytoplasm for reproduction, and regulating the respiratory burst for immune system response. It is no wonder that in acidic environments such as the tumor microenvironment, an exacerbated expression and function of this channel has been reported. Indeed, multiple studies have revealed a strong relationship between pH balance, cancer development, and the overexpression of the Hv1 channel, being proposed as a marker for malignancy in cancer. In this review, we present data that supports the idea that the Hv1 channel plays a significant role in cancer by maintaining pH conditions that favor the development of malignancy features in solid tumor models. With the antecedents presented in this bibliographic report, we want to strengthen the idea that the Hv1 proton channel is an excellent therapeutic strategy to counter the development of solid tumors.
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Affiliation(s)
- Juan J. Alvear-Arias
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Millennium Nucleus in NanoBioPhysics, Universidad de Valparaíso, Valparaíso, Chile
| | - Antonio Pena-Pichicoi
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Millennium Nucleus in NanoBioPhysics, Universidad de Valparaíso, Valparaíso, Chile
| | - Christian Carrillo
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Millennium Nucleus in NanoBioPhysics, Universidad de Valparaíso, Valparaíso, Chile
| | - Miguel Fernandez
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Millennium Nucleus in NanoBioPhysics, Universidad de Valparaíso, Valparaíso, Chile
| | - Tania Gonzalez
- National Center for Minimally Invasive Surgery, La Habana, Cuba
| | - Jose A. Garate
- Millennium Nucleus in NanoBioPhysics, Universidad de Valparaíso, Valparaíso, Chile
- Facultad de Ingeniería y Tecnología, Universidad San Sebastián, Santiago, Chile
- Centro Científico y Tecnológico de Excelencia Ciencia y Vida, Santiago, Chile
| | - Carlos Gonzalez
- Centro Interdisciplinario de Neurociencia de Valparaíso, Universidad de Valparaíso, Valparaíso, Chile
- Millennium Nucleus in NanoBioPhysics, Universidad de Valparaíso, Valparaíso, Chile
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, United States
- *Correspondence: Carlos Gonzalez,
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16
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Duan Q, Zhang S, Wang Y, Lu D, Sun Y, Wu Y. Proton-coupled monocarboxylate transporters in cancer: From metabolic crosstalk, immunosuppression and anti-apoptosis to clinical applications. Front Cell Dev Biol 2022; 10:1069555. [PMID: 36506099 PMCID: PMC9727313 DOI: 10.3389/fcell.2022.1069555] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/02/2022] [Indexed: 11/24/2022] Open
Abstract
The Warburg effect is known as the hyperactive glycolysis that provides the energy needed for rapid growth and proliferation in most tumor cells even under the condition of sufficient oxygen. This metabolic pattern can lead to a large accumulation of lactic acid and intracellular acidification, which can affect the growth of tumor cells and lead to cell death. Proton-coupled monocarboxylate transporters (MCTs) belong to the SLC16A gene family, which consists of 14 members. MCT1-4 promotes the passive transport of monocarboxylate (e.g., lactate, pyruvate, and ketone bodies) and proton transport across membranes. MCT1-4-mediated lactate shuttling between glycolytic tumor cells or cancer-associated fibroblasts and oxidative tumor cells plays an important role in the metabolic reprogramming of energy, lipids, and amino acids and maintains the survival of tumor cells. In addition, MCT-mediated lactate signaling can promote tumor angiogenesis, immune suppression and multidrug resistance, migration and metastasis, and ferroptosis resistance and autophagy, which is conducive to the development of tumor cells and avoid death. Although there are certain challenges, the study of targeted drugs against these transporters shows great promise and may form new anticancer treatment options.
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Affiliation(s)
- Qixin Duan
- Department of Urology, Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China,Department of Urology, Nanyang Central Hospital, Nanyang, China
| | - Shuang Zhang
- Department of Nursing, Nanyang Central Hospital, Nanyang, China
| | - Yang Wang
- Department of Urology, Nanyang Central Hospital, Nanyang, China
| | - Dongming Lu
- Department of Urology, Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China
| | - Yingming Sun
- Department of Medical and Radiation Oncology, Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China,*Correspondence: Yongyang Wu, ; Yingming Sun,
| | - Yongyang Wu
- Department of Urology, Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China,*Correspondence: Yongyang Wu, ; Yingming Sun,
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17
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Hiltunen N, Rintala J, Väyrynen JP, Böhm J, Karttunen TJ, Huhta H, Helminen O. Monocarboxylate Transporters 1 and 4 and Prognosis in Small Bowel Neuroendocrine Tumors. Cancers (Basel) 2022; 14:2552. [PMID: 35626155 PMCID: PMC9139933 DOI: 10.3390/cancers14102552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/09/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022] Open
Abstract
Monocarboxylate transporters (MCTs) are cell membrane proteins transporting lactate, pyruvate, and ketone bodies across the plasma membrane. The prognostic role of MCTs in neuroendocrine tumors is unknown. We aimed to analyze MCT1 and MCT4 expression in small bowel neuroendocrine tumors (SB-NETs). The cohort included 109 SB-NETs and 61 SB-NET lymph node metastases from two Finnish hospitals. Tumor samples were immunohistochemically stained with MCT1 and MCT4 monoclonal antibodies. The staining intensity, percentage of positive cells, and stromal staining were assessed. MCT1 and MCT4 scores (0, 1 or 2) were composed based on the staining intensity and the percentage of positive cells. Survival analyses were performed with the Kaplan-Meier method and Cox regression, adjusted for confounders. The primary outcome was disease-specific survival (DSS). A high MCT4 intensity in SB-NETs was associated with better DSS when compared to low intensity (85.7 vs. 56.6%, p = 0.020). A high MCT4 percentage of positive cells resulted in better DSS when compared to a low percentage (77.4 vs. 49.1%, p = 0.059). MCT4 scores 0, 1, and 2 showed DSS of 52.8 vs. 58.8 vs. 100% (p = 0.025), respectively. After adjusting for confounders, the mortality hazard was lowest in the patients with a high MCT4 score. MCT1 showed no association with survival. According to our study, a high MCT4 expression is associated with an improved prognosis in SB-NETs.
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Affiliation(s)
- Niko Hiltunen
- Cancer and Translational Medicine Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland; (J.R.); (J.P.V.); (T.J.K.); (H.H.); (O.H.)
| | - Jukka Rintala
- Cancer and Translational Medicine Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland; (J.R.); (J.P.V.); (T.J.K.); (H.H.); (O.H.)
- Surgery Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland
| | - Juha P. Väyrynen
- Cancer and Translational Medicine Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland; (J.R.); (J.P.V.); (T.J.K.); (H.H.); (O.H.)
| | - Jan Böhm
- Department of Pathology, Central Finland Central Hospital, 40620 Jyväskylä, Finland;
| | - Tuomo J. Karttunen
- Cancer and Translational Medicine Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland; (J.R.); (J.P.V.); (T.J.K.); (H.H.); (O.H.)
| | - Heikki Huhta
- Cancer and Translational Medicine Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland; (J.R.); (J.P.V.); (T.J.K.); (H.H.); (O.H.)
| | - Olli Helminen
- Cancer and Translational Medicine Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland; (J.R.); (J.P.V.); (T.J.K.); (H.H.); (O.H.)
- Surgery Research Unit, Medical Research Center, Oulu University Hospital and University of Oulu, 90220 Oulu, Finland
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18
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Choi JW, Lee Y, Kim H, Cho HY, Min SK, Kim YS. Coexpression of MCT1 and MCT4 in ALK-positive Anaplastic Large Cell Lymphoma: Diagnostic and Therapeutic Implications. Am J Surg Pathol 2022; 46:241-248. [PMID: 34619707 DOI: 10.1097/pas.0000000000001820] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
In solid tumors, glycolytic cancer or stromal cells export lactates through monocarboxylate transporter (MCT) 4, while oxidative cancer or stromal cells take up lactates as metabolic fuels or signaling molecules through MCT1. CD147 acts as a chaperone of MCT1 or MCT4. Unlike solid tumors, malignant lymphomas have a peculiar tumor microenvironment. To investigate the metabolic phenotype of malignant lymphoma associated with lactate transport, we analyzed immunohistochemical expressions of MCT1, MCT4, and CD147 in 247 cases of various malignant lymphomas. Surprisingly, both MCT1 and MCT4 were diffusely expressed on tumor cell membranes in all cases (11/11, 100%) of anaplastic lymphoma kinase (ALK) (+) anaplastic large cell lymphoma (ALCL). In contrast, only MCT1 was diffusely expressed in tumor cells of ALK(-) ALCL, as well as in B-cell, natural killer/T-cell, T-cell, and classic Hodgkin lymphomas. In these lymphomas, MCT4 expression was mostly localized to adjacent stromal cells. The pattern of diffuse membranous MCT1 and partial MCT4 expressions in tumor cells was observed in 1 case each of peripheral T-cell lymphoma (1/15, 6.7%) and multiple myeloma (1/34, 2.9%). CD147 was diffusely expressed in all types of lymphoma tumor and/or stromal cells. In conclusion, ALK(+) ALCL has a unique metabolism showing high coexpression of MCT1 and MCT4 in tumor cells. Because only ALK(+) ALCL overexpresses MCT4, immunostaining for MCT4 together with ALK is very useful for differential diagnosis from ALK(-) ALCL or peripheral T-cell lymphoma. Moreover, dual targeting against MCT1 and MCT4 would be an appropriate therapeutic approach for ALK(+) ALCL.
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MESH Headings
- Anaplastic Lymphoma Kinase/analysis
- Anaplastic Lymphoma Kinase/genetics
- Basigin/analysis
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Clinical Decision-Making
- Humans
- Immunohistochemistry
- In Situ Hybridization
- Lymphoma, Large-Cell, Anaplastic/enzymology
- Lymphoma, Large-Cell, Anaplastic/genetics
- Lymphoma, Large-Cell, Anaplastic/pathology
- Lymphoma, Large-Cell, Anaplastic/therapy
- Monocarboxylic Acid Transporters/analysis
- Monocarboxylic Acid Transporters/genetics
- Muscle Proteins/analysis
- Muscle Proteins/genetics
- Predictive Value of Tests
- Prognosis
- Republic of Korea
- Symporters/analysis
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Affiliation(s)
- Jung-Woo Choi
- Department of Pathology, Korea University Ansan Hospital, Ansan
| | - Youngseok Lee
- Department of Pathology, Korea University Anam Hospital, Seoul
| | - Hyunchul Kim
- Department of Pathology, Cha University Ilsan Medical Center, Goyang
| | - Hyun Yee Cho
- Department of Pathology, Korea University Anam Hospital, Seoul
| | - Soo Kee Min
- Department of Pathology, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea
| | - Young-Sik Kim
- Department of Pathology, Korea University Ansan Hospital, Ansan
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19
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Sushentsev N, McLean MA, Warren AY, Benjamin AJV, Brodie C, Frary A, Gill AB, Jones J, Kaggie JD, Lamb BW, Locke MJ, Miller JL, Mills IG, Priest AN, Robb FJL, Shah N, Schulte RF, Graves MJ, Gnanapragasam VJ, Brindle KM, Barrett T, Gallagher FA. Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer. Nat Commun 2022; 13:466. [PMID: 35075123 PMCID: PMC8786834 DOI: 10.1038/s41467-022-28069-2] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023] Open
Abstract
Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.
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Affiliation(s)
- Nikita Sushentsev
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Mary A McLean
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Anne Y Warren
- Department of Pathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Arnold J V Benjamin
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Cara Brodie
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Amy Frary
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Andrew B Gill
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Julia Jones
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Joshua D Kaggie
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Benjamin W Lamb
- Department of Urology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- School of Allied Health, Anglia Ruskin University, Cambridge, UK
| | - Matthew J Locke
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Jodi L Miller
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Ian G Mills
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, UK
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
- Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Andrew N Priest
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | | | - Nimish Shah
- Department of Urology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Martin J Graves
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
| | - Vincent J Gnanapragasam
- Department of Urology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Division of Urology, Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Urology Translational Research and Clinical Trials Office, Cambridge Biomedical Campus, Addenbrooke's Hospital, Cambridge, UK
| | - Kevin M Brindle
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
- Department of Biochemistry, University of Cambridge, Cambridge, UK
| | - Tristan Barrett
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK.
| | - Ferdia A Gallagher
- Department of Radiology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK
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20
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Sebestyén A, Dankó T, Sztankovics D, Moldvai D, Raffay R, Cervi C, Krencz I, Zsiros V, Jeney A, Petővári G. The role of metabolic ecosystem in cancer progression — metabolic plasticity and mTOR hyperactivity in tumor tissues. Cancer Metastasis Rev 2022; 40:989-1033. [PMID: 35029792 PMCID: PMC8825419 DOI: 10.1007/s10555-021-10006-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 11/26/2021] [Indexed: 12/14/2022]
Abstract
Despite advancements in cancer management, tumor relapse and metastasis are associated with poor outcomes in many cancers. Over the past decade, oncogene-driven carcinogenesis, dysregulated cellular signaling networks, dynamic changes in the tissue microenvironment, epithelial-mesenchymal transitions, protein expression within regulatory pathways, and their part in tumor progression are described in several studies. However, the complexity of metabolic enzyme expression is considerably under evaluated. Alterations in cellular metabolism determine the individual phenotype and behavior of cells, which is a well-recognized hallmark of cancer progression, especially in the adaptation mechanisms underlying therapy resistance. In metabolic symbiosis, cells compete, communicate, and even feed each other, supervised by tumor cells. Metabolic reprogramming forms a unique fingerprint for each tumor tissue, depending on the cellular content and genetic, epigenetic, and microenvironmental alterations of the developing cancer. Based on its sensing and effector functions, the mechanistic target of rapamycin (mTOR) kinase is considered the master regulator of metabolic adaptation. Moreover, mTOR kinase hyperactivity is associated with poor prognosis in various tumor types. In situ metabolic phenotyping in recent studies highlights the importance of metabolic plasticity, mTOR hyperactivity, and their role in tumor progression. In this review, we update recent developments in metabolic phenotyping of the cancer ecosystem, metabolic symbiosis, and plasticity which could provide new research directions in tumor biology. In addition, we suggest pathomorphological and analytical studies relating to metabolic alterations, mTOR activity, and their associations which are necessary to improve understanding of tumor heterogeneity and expand the therapeutic management of cancer.
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21
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Wang Y, Qin L, Chen W, Chen Q, Sun J, Wang G. Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1. Eur J Med Chem 2021; 226:113806. [PMID: 34517305 DOI: 10.1016/j.ejmech.2021.113806] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 02/08/2023]
Abstract
Poor selectivity, potential systemic toxicity and drug resistance are the main challenges associated with chemotherapeutic drugs. MCT1 and MCT4 and LAT1 play vital roles in tumour metabolism and growth by taking up nutrients and are thus potential targets for tumour therapy. An increasing number of studies have shown the feasibility of including these transporters as components of tumour-targeting therapy. Here, we summarize the recent progress in MCT1-, MCT4-and LAT1-based therapeutic strategies. First, protein structures, expression, relationships with cancer, and substrate characteristics are introduced. Then, different drug targeting and delivery strategies using these proteins have been reviewed, including designing protein inhibitors, prodrugs and nanoparticles. Finally, a dual targeted strategy is discussed because these proteins exert a synergistic effect on tumour proliferation. This article concentrates on tumour treatments targeting MCT1, MCT4 and LAT1 and delivery techniques for improving the antitumour effect. These innovative tactics represent current state-of-the-art developments in transporter-based antitumour drugs.
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Affiliation(s)
- Yang Wang
- Personnel Department, Guang Xi University of Chinese Medicine, Nanning, 530200, PR China
| | - Liuxin Qin
- School of Pharmacy, Guang Xi University of Chinese Medicine, Nanning, 530200, PR China
| | - Weiwei Chen
- School of Pharmacy, Guang Xi University of Chinese Medicine, Nanning, 530200, PR China
| | - Qing Chen
- Zhuang Yao Medicine Center of Engineering and Technology, Guang Xi University of Chinese Medicine, Nanning, 530200, PR China
| | - Jin Sun
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, China
| | - Gang Wang
- Zhuang Yao Medicine Center of Engineering and Technology, Guang Xi University of Chinese Medicine, Nanning, 530200, PR China.
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22
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de Carvalho PA, Bonatelli M, Cordeiro MD, Coelho RF, Reis S, Srougi M, Nahas WC, Pinheiro C, Leite KRM. MCT1 expression is independently related to shorter cancer-specific survival in clear cell renal cell carcinoma. Carcinogenesis 2021; 42:1420-1427. [PMID: 34668521 DOI: 10.1093/carcin/bgab100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/05/2021] [Accepted: 10/18/2021] [Indexed: 11/15/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) has been considered a metabolic disease, with loss of von Hippel-Lindau (VHL) gene and consequent overexpression of hypoxia-inducible factor 1 alpha (HIF-1α), which is central for tumor development and progression. Among other effects, HIF-1α is involved in the metabolic reprogramming of cancer cells towards the Warburg effect involved in tumor cell proliferation, migration and survival. In this context, several proteins are expressed by cancer cells, including glucose and lactate transporters as well as different pH regulators. Among them, monocarboxylate transporters (MCTs) can be highlighted. Our aim is to comprehensively analyze the immunoexpression of MCT1, MCT2, MCT4, CD147, CD44, HIF-1α, GLUT1 and CAIX in ccRCC surgical specimens correlating with classical prognostic factors and survival of patients with long follow up. Surgical specimens from 207 patients with ccRCC who underwent radical or partial nephrectomy were used to build a tissue microarray. Immunostaining was categorized into absent/weak or moderate/strong and related to all classic ccRCC prognostic parameters. Kaplan-Meier curves were generated to assess overall and cancer-specific survival, and multivariate analysis was performed to identify independent prognostic factors of survival. Multivariate analysis showed that MCT1 together with tumor size and TNM staging, were independently related to cancer-specific survival. MCT1, CD147, CD44 and GLUT1 expression were significantly associated with poor prognostic factors. We show that MCT1 is an independent prognostic factor for cancer-specific survival in ccRCC justifying the use of new target therapies already being tested in clinical trials.
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Affiliation(s)
- Paulo Afonso de Carvalho
- Faculdade de Medicina da Universidade de Sao Paulo, Laboratory of Medical Investigation (LIM55)-Urology Department, Sao Paulo, Brazil
- Instituto do Câncer do Estado de Sao Paulo (ICESP), Sao Paulo, Brazil
| | - Murilo Bonatelli
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil
| | | | | | - Sabrina Reis
- Faculdade de Medicina da Universidade de Sao Paulo, Laboratory of Medical Investigation (LIM55)-Urology Department, Sao Paulo, Brazil
| | - Miguel Srougi
- Faculdade de Medicina da Universidade de Sao Paulo, Laboratory of Medical Investigation (LIM55)-Urology Department, Sao Paulo, Brazil
- Instituto do Câncer do Estado de Sao Paulo (ICESP), Sao Paulo, Brazil
| | - Willian Carlos Nahas
- Faculdade de Medicina da Universidade de Sao Paulo, Laboratory of Medical Investigation (LIM55)-Urology Department, Sao Paulo, Brazil
- Instituto do Câncer do Estado de Sao Paulo (ICESP), Sao Paulo, Brazil
| | - Celine Pinheiro
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil
- Barretos School of Health Sciences Dr. Paulo Prata-FACISB, Barretos, Sao Paulo, Brazil
| | - Katia Ramos Moreira Leite
- Faculdade de Medicina da Universidade de Sao Paulo, Laboratory of Medical Investigation (LIM55)-Urology Department, Sao Paulo, Brazil
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Yang M, Zhong X, Yuan Y. Does Baking Soda Function as a Magic Bullet for Patients With Cancer? A Mini Review. Integr Cancer Ther 2021; 19:1534735420922579. [PMID: 32448009 PMCID: PMC7249593 DOI: 10.1177/1534735420922579] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Sodium bicarbonate, commonly known as baking soda, is widely used in the clinic
as an antacid for treating gastric hyperacidity, among other conditions. Chao et
al have reported a clinical trial about targeting intratumor lactic
acidosis–transarterial chemoembolization. Based on conventional transarterial
chemoembolization, the authors added a 5% sodium bicarbonate solution to
cytotoxic drugs, resulting in a high local control rate. The explanation for the
antitumor effects of sodium bicarbonate is related to acidosis in the tumor
microenvironment. In this review, we summarize the findings from studies
administering sodium bicarbonate alone or in combination with other anticancer
therapies as cancer treatments, and discuss methods for safe and effective use
of sodium bicarbonate in the clinic.
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Affiliation(s)
- Mengyuan Yang
- The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xian Zhong
- The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ying Yuan
- The Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China
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24
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Chandel V, Kumar D. Targeting Signalling Cross-Talk between Cancer Cells and Cancer-Associated Fibroblast through Monocarboxylate Transporters in Head and Neck Cancer. Anticancer Agents Med Chem 2021; 21:1369-1378. [PMID: 32698754 DOI: 10.2174/1871520620666200721135230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 11/22/2022]
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive malignancy affecting more than 600,000 cases worldwide annually, associated with poor prognosis and significant morbidity. HNSCC tumors are dysplastic, with up to 80% fibroblasts. It has been reported that Cancer-Associated Fibroblasts (CAFs) facilitate HNSCC progression. Unlike normal cells, malignant cells often display increased glycolysis, even in the presence of oxygen; a phenomenon known as the Warburg effect. As a consequence, there is an increase in Lactic Acid (LA) production. Earlier, it has been reported that HNSCC tumors exhibit high LA levels that correlate with reduced survival. It has been reported that the activation of the receptor tyrosine kinase, c- MET, by CAF-secreted Hepatocyte Growth Factor (HGF) is a major contributing event in the progression of HNSCC. In nasopharyngeal carcinoma, c-MET inhibition downregulates the TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) and NADPH production resulting in apoptosis. Previously, it was demonstrated that HNSCC tumor cells are highly glycolytic. Further, CAFs show a higher capacity to utilize LA as a carbon source to fuel mitochondrial respiration than HNSCC. Earlier, we have reported that in admixed cultures, both cell types increase the expression of Monocarboxylate Transporters (MCTs) for a bidirectional LA transporter. Consequently, MCTs play an important role in signalling cross-talk between cancer cells and cancer associate fibroblast in head and neck cancer, and targeting MCTs would lead to the development of a potential therapeutic approach for head and neck cancer. In this review, we focus on the regulation of MCTs in head and neck cancer through signalling cross-talk between cancer cells and cancer-associated fibroblasts, and targeting this signalling cross talk would lead to the development of a potential therapeutic approach for head and neck cancer.
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Affiliation(s)
- Vaishali Chandel
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida-201313, (UP), India
| | - Dhruv Kumar
- Amity Institute of Molecular Medicine & Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sec-125, Noida-201313, (UP), India
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Xie W, Guo H, Zhang J, Hu L, Wu Y, Wang X. Comprehensive Analysis of the Relationship Between Metabolic Reprogramming and Immune Function in Prostate Cancer. Onco Targets Ther 2021; 14:3251-3266. [PMID: 34040390 PMCID: PMC8140915 DOI: 10.2147/ott.s304298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 05/04/2021] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Prostate cancer is the most common malignant urinary tumor among men. Treatments are currently unsatisfactory for advanced prostate cancer. Cancer biology remains the basis for developing new antitumor drugs. Therefore, it is crucial to study the metabolic reprogramming, immune microenvironment, and immune evasion of tumors. This study aimed to clarify the relationship between tumor glycolysis and immune function in prostate cancer. MATERIALS AND METHODS We downloaded the gene expression matrix and clinical data of prostate cancer from The Cancer Genome Atlas. We studied the expression profiles and prognostic significance of glycolysis-related genes and used CIBERSORT to identify the proportion of tumor-infiltrating immune cells. Through differential gene expression analysis, gene ontology analysis, Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis, and correlation analysis, we further explored the relationship between glycolytic activity and immune function. We also performed immunohistochemistry, Western blot and RT-qPCR experiments using human prostate cancer tissue and cell lines to verify the expression of some glycolytic genes, macrophage infiltration and polarization. RESULTS Among glycolysis-related genes, the expression of SLC16A3 in prostate cancer tissues was lower than that in normal tissues, but its high expression was associated with poor prognosis. In the high SLC16A3 expression group, several glycolysis-related genes also showed high expression, which was confirmed by immunohistochemistry experiments and Western blot. In high-glycolysis group, the expression of immune-related genes and the interleukin-17 (IL-17) signaling pathway were upregulated. CD8+ T cells, regulatory T cells, macrophages, and other immune cells were highly enriched. Among them, M2 macrophage infiltration was associated with poor prognosis. CONCLUSION The enhanced glycolytic activity of prostate cancer may contribute to the formation of a pro-tumor immune microenvironment. The IL-17 signaling pathway may play an important mediating role in the interaction between tumor glycolysis and immune function.
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Affiliation(s)
- Weijie Xie
- Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Huan Guo
- Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Jiawei Zhang
- Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Li Hu
- Department of Physiology, Shantou University of Medical College, Shantou, People’s Republic of China
| | - Yuqi Wu
- Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
| | - Xiangwei Wang
- Department of Urology & Carson International Cancer Center, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy Center, Shenzhen University, Shenzhen, People’s Republic of China
- Department of Urology, 3rd Affiliated Hospital and Department of Perioperative Medicine of Southern University of Science and Technology, Southern University of Science and Technology, Shenzhen, People’s Republic of China
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Stepka P, Vsiansky V, Raudenska M, Gumulec J, Adam V, Masarik M. Metabolic and Amino Acid Alterations of the Tumor Microenvironment. Curr Med Chem 2021; 28:1270-1289. [PMID: 32031065 DOI: 10.2174/0929867327666200207114658] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/13/2020] [Accepted: 01/17/2020] [Indexed: 11/22/2022]
Abstract
Metabolic changes driven by the hostile tumor microenvironment surrounding cancer cells and the effect of these changes on tumorigenesis and metastatic potential have been known for a long time. The usual point of interest is glucose and changes in its utilization by cancer cells, mainly in the form of the Warburg effect. However, amino acids, both intra- and extracellular, also represent an important aspect of tumour microenvironment, which can have a significant effect on cancer cell metabolism and overall development of the tumor. Namely, alterations in the metabolism of amino acids glutamine, sarcosine, aspartate, methionine and cysteine have been previously connected to the tumor progression and aggressivity of cancer. The aim of this review is to pinpoint current gaps in our knowledge of the role of amino acids as a part of the tumor microenvironment and to show the effect of various amino acids on cancer cell metabolism and metastatic potential. This review shows limitations and exceptions from the traditionally accepted model of Warburg effect in some cancer tissues, with the emphasis on prostate cancer, because the traditional definition of Warburg effect as a metabolic switch to aerobic glycolysis does not always apply. Prostatic tissue both in a healthy and transformed state significantly differs in many metabolic aspects, including the metabolisms of glucose and amino acids, from the metabolism of other tissues. Findings from different tissues are, therefore, not always interchangeable and have to be taken into account during experimentation modifying the environment of tumor tissue by amino acid supplementation or depletion, which could potentially serve as a new therapeutic approach.
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Affiliation(s)
- Petr Stepka
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Vit Vsiansky
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Jaromir Gumulec
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-62500 Brno, Czech Republic
| | - Vojtech Adam
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-61600 Brno, Czech Republic
| | - Michal Masarik
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-61600 Brno, Czech Republic
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Kobayashi M, Narumi K, Furugen A, Iseki K. Transport function, regulation, and biology of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4). Pharmacol Ther 2021; 226:107862. [PMID: 33894276 DOI: 10.1016/j.pharmthera.2021.107862] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Revised: 04/08/2021] [Accepted: 04/08/2021] [Indexed: 12/20/2022]
Abstract
Human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4) are involved in the proton-dependent transport of monocarboxylates such as L-lactate, which play an essential role in cellular metabolism and pH regulation. hMCT1 and 4 are overexpressed in a number of cancers, and polymorphisms in hMCT1 have been reported to be associated with the prognosis of some cancers. Accordingly, recent advances have focused on the inhibition of these transporters as a novel therapeutic strategy in cancers. To screen for MCT inhibitors for clinical application, it is important to study MCT function and regulation, and the effect of compounds on them, using human-derived cells. In this review, we focus on the transport function, regulation, and biology of hMCT1 and hMCT4, and the effects of genetic variation in these transporters in humans.
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Affiliation(s)
- Masaki Kobayashi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan; Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan.
| | - Katsuya Narumi
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Ayako Furugen
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan
| | - Ken Iseki
- Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
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Becker HM, Deitmer JW. Proton Transport in Cancer Cells: The Role of Carbonic Anhydrases. Int J Mol Sci 2021; 22:ijms22063171. [PMID: 33804674 PMCID: PMC8003680 DOI: 10.3390/ijms22063171] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Intra- and extracellular pH regulation is a pivotal function of all cells and tissues. Net outward transport of H+ is a prerequisite for normal physiological function, since a number of intracellular processes, such as metabolism and energy supply, produce acid. In tumor tissues, distorted pH regulation results in extracellular acidification and the formation of a hostile environment in which cancer cells can outcompete healthy local host cells. Cancer cells employ a variety of H+/HCO3−-coupled transporters in combination with intra- and extracellular carbonic anhydrase (CA) isoforms, to alter intra- and extracellular pH to values that promote tumor progression. Many of the transporters could closely associate to CAs, to form a protein complex coined “transport metabolon”. While transport metabolons built with HCO3−-coupled transporters require CA catalytic activity, transport metabolons with monocarboxylate transporters (MCTs) operate independently from CA catalytic function. In this article, we assess some of the processes and functions of CAs for tumor pH regulation and discuss the role of intra- and extracellular pH regulation for cancer pathogenesis and therapeutic intervention.
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Affiliation(s)
- Holger M. Becker
- Zoology and Animal Physiology, Institute of Zoology, TU Dresden, D-01217 Dresden, Germany
- Correspondence:
| | - Joachim W. Deitmer
- Department of Biology, University of Kaiserslautern, D-67653 Kaiserslautern, Germany;
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Tong YH, Hu XP, Xiang XP, Fang L. High expression of monocarboxylate transporter 4 (MCT 4), but not MCT 1, predicts poor prognosis in patients with non-small cell lung cancer. Transl Cancer Res 2021; 10:1336-1345. [PMID: 35116459 PMCID: PMC8798489 DOI: 10.21037/tcr-20-3117] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/27/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND The monocarboxylate transporter (MCT) family especially MCT1 and MCT4 have been recognized to play an important role in lactate transport, a key glycolytic product. The expression of MCT1 and MCT4 expression was previously found to be related to poor outcome in various cancer types. In this study, we investigated the expression status of MCT1 and MCT4 and their relationship with prognosis in non-small cell lung cancer (NSCLC). METHODS Expression of MCT4 and MCT1 in NSCLC tumor and adjacent lung tissues were detected by immunohistochemistry. Kaplan-Meier plots were used to evaluate two proteins' prognostic role, and the log-rank test obtained the P value. For multivariate analysis, the Cox proportional-hazards regression method was performed. RESULTS High MCT4 and MCT1 expression was observed in cancer cells, with a rate of 45% for MCT4 versus 15% for MCT1 among all NSCLC patients. High expression of MCT4, and not MCT1, was associated with worse overall survival (OS) [hazard ratio (HR) =1.96 (1.06-3.75), P=0.032] and progression-free survival (PFS) [HR =1.72 (1.05-2.93), P=0.032] in NSCLC patients. In our multivariate analysis, advanced cancer stage and high MCT4 level were identified as independent predictive indicators for both PFS [HR(MCT4) =1.888 (1.114-3.199), P=0.018 and OS [HR (MCT4) =2.421 (1.271-4.610), P=0.007]. Subgroup and interaction analyses were also performed in different clinical characteristic groups and no significant differences were observed. CONCLUSIONS High MCT4 expression is a predictive marker for worse outcome in NSCLC patients.
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Affiliation(s)
- Ying-Hui Tong
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiao-Ping Hu
- Department of Pharmacy, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Xue-Ping Xiang
- Department of Pathology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Luo Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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The Harmonious Interplay of Amino Acid and Monocarboxylate Transporters Induces the Robustness of Cancer Cells. Metabolites 2021; 11:metabo11010027. [PMID: 33401672 PMCID: PMC7823946 DOI: 10.3390/metabo11010027] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/26/2020] [Accepted: 12/27/2020] [Indexed: 02/07/2023] Open
Abstract
There is a growing body of evidence that metabolic reprogramming contributes to the acquisition and maintenance of robustness associated with malignancy. The fine regulation of expression levels of amino acid and monocarboxylate transporters enables cancer cells to exhibit the metabolic reprogramming that is responsible for therapeutic resistance. Amino acid transporters characterized by xCT (SLC7A11), ASCT2 (SLC1A5), and LAT1 (SLC7A5) function in the uptake and export of amino acids such as cystine and glutamine, thereby regulating glutathione synthesis, autophagy, and glutaminolysis. CD44 variant, a cancer stem-like cell marker, stabilizes the xCT antiporter at the cellular membrane, and tumor cells positive for xCT and/or ASCT2 are susceptible to sulfasalazine, a system Xc(-) inhibitor. Inhibiting the interaction between LAT1 and CD98 heavy chain prevents activation of the mammalian target of rapamycin (mTOR) complex 1 by glutamine and leucine. mTOR signaling regulated by LAT1 is a sensor of dynamic alterations in the nutrient tumor microenvironment. LAT1 is overexpressed in various malignancies and positively correlated with poor clinical outcome. Metabolic reprogramming of glutamine occurs often in cancer cells and manifests as ASCT2-mediated glutamine addiction. Monocarboxylate transporters (MCTs) mediate metabolic symbiosis, by which lactate in cancer cells under hypoxia is exported through MCT4 and imported by MCT1 in less hypoxic regions, where it is used as an oxidative metabolite. Differential expression patterns of transporters cause functional intratumoral heterogeneity leading to the therapeutic resistance. Therefore, metabolic reprogramming based on these transporters may be a promising therapeutic target. This review highlights the pathological function and therapeutic targets of transporters including xCT, ASCT2, LAT1, and MCT.
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Targeting Cancer Metabolism and Current Anti-Cancer Drugs. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1286:15-48. [PMID: 33725343 DOI: 10.1007/978-3-030-55035-6_2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Several studies have exploited the metabolic hallmarks that distinguish between normal and cancer cells, aiming at identifying specific targets of anti-cancer drugs. It has become apparent that metabolic flexibility allows cancer cells to survive during high anabolic demand or the depletion of nutrients and oxygen. Cancers can reprogram their metabolism to the microenvironments by increasing aerobic glycolysis to maximize ATP production, increasing glutaminolysis and anabolic pathways to support bioenergetic and biosynthetic demand during rapid proliferation. The increased key regulatory enzymes that support the relevant pathways allow us to design small molecules which can specifically block activities of these enzymes, preventing growth and metastasis of tumors. In this review, we discuss metabolic adaptation in cancers and highlight the crucial metabolic enzymes involved, specifically those involved in aerobic glycolysis, glutaminolysis, de novo fatty acid synthesis, and bioenergetic pathways. Furthermore, we also review the success and the pitfalls of the current anti-cancer drugs which have been applied in pre-clinical and clinical studies.
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Koltai T. Targeting the pH Paradigm at the Bedside: A Practical Approach. Int J Mol Sci 2020; 21:E9221. [PMID: 33287221 PMCID: PMC7730959 DOI: 10.3390/ijms21239221] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
The inversion of the pH gradient in malignant tumors, known as the pH paradigm, is increasingly becoming accepted by the scientific community as a hallmark of cancer. Accumulated evidence shows that this is not simply a metabolic consequence of a dysregulated behavior, but rather an essential process in the physiopathology of accelerated proliferation and invasion. From the over-simplification of increased lactate production as the cause of the paradigm, as initially proposed, basic science researchers have arrived at highly complex and far-reaching knowledge, that substantially modified that initial belief. These new developments show that the paradigm entails a different regulation of membrane transporters, electrolyte exchangers, cellular and membrane enzymes, water trafficking, specialized membrane structures, transcription factors, and metabolic changes that go far beyond fermentative glycolysis. This complex world of dysregulations is still shuttered behind the walls of experimental laboratories and has not yet reached bedside medicine. However, there are many known pharmaceuticals and nutraceuticals that are capable of targeting the pH paradigm. Most of these products are well known, have low toxicity, and are also inexpensive. They need to be repurposed, and this would entail shorter clinical studies and enormous cost savings if we compare them with the time and expense required for the development of a new molecule. Will targeting the pH paradigm solve the "cancer problem"? Absolutely not. However, reversing the pH inversion would strongly enhance standard treatments, rendering them more efficient, and in some cases permitting lower doses of toxic drugs. This article's goal is to describe how to reverse the pH gradient inversion with existing drugs and nutraceuticals that can easily be used in bedside medicine, without adding toxicity to established treatments. It also aims at increasing awareness among practicing physicians that targeting the pH paradigm would be able to improve the results of standard therapies. Some clinical cases will be presented as well, showing how the pH gradient inversion can be treated at the bedside in a simple manner with repurposed drugs.
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Affiliation(s)
- Tomas Koltai
- Centro de Diagnostico y Tratamiento de la Obra Social del Personal de la Alimentacion, Talar de Pacheco, Buenos Aires 1617, Argentina
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Himbert D, Zeuschner P, Ayoubian H, Heinzelmann J, Stöckle M, Junker K. Characterization of CD147, CA9, and CD70 as Tumor-Specific Markers on Extracellular Vesicles in Clear Cell Renal Cell Carcinoma. Diagnostics (Basel) 2020; 10:diagnostics10121034. [PMID: 33276608 PMCID: PMC7761541 DOI: 10.3390/diagnostics10121034] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 11/29/2020] [Indexed: 01/04/2023] Open
Abstract
Extracellular vesicles (EVs) are secreted by healthy and tumor cells and are involved in cell–cell communication. Tumor-released EVs could represent a new class of biomarkers from liquid biopsies. The aim of this study was to identify tumor-specific EV markers in clear cell renal carcinoma (ccRCC) using cell lines and patient-derived tissue samples. EVs from ccRCC cell lines (786-O, RCC53, Caki1, and Caki2) and patient tissues were isolated via ultracentrifugation. EVs were characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting using exosome and putative tumor markers (epithelial cell adhesion molecule (EpCAM), carbonic anhydrase 9 (CA9), CD70, CD147). The tumor markers were verified using immunohistochemistry. CA9 was expressed in Caki2 cells and EVs, and CD147 was found in the cells and EVs of all tested ccRCC cell lines. In tumor tissues, we found an increased expression of CA9, CD70, and CD147 were increased in cell lysates and EV fractions compared to normal tissues. In contrast, EpCAM was heterogeneously expressed in tumor samples and positive in normal tissue. To conclude, we developed an effective technique to isolate EVs directly from human tissue samples with high purity and high concentration. In contrast to EpCAM, CA9, CD70, and CD147 could represent promising markers to identify tumor-specific EVs in ccRCC.
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Affiliation(s)
- Dirk Himbert
- Department of Urology and Pediatric Urology, Saarland University, 66421 Homburg/Saar, Germany; (D.H.); (P.Z.); (H.A.); (J.H.); (M.S.)
| | - Philip Zeuschner
- Department of Urology and Pediatric Urology, Saarland University, 66421 Homburg/Saar, Germany; (D.H.); (P.Z.); (H.A.); (J.H.); (M.S.)
| | - Hiresh Ayoubian
- Department of Urology and Pediatric Urology, Saarland University, 66421 Homburg/Saar, Germany; (D.H.); (P.Z.); (H.A.); (J.H.); (M.S.)
| | - Joana Heinzelmann
- Department of Urology and Pediatric Urology, Saarland University, 66421 Homburg/Saar, Germany; (D.H.); (P.Z.); (H.A.); (J.H.); (M.S.)
- Department of Ophthalmology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, 06108 Halle/Saale, Germany
| | - Michael Stöckle
- Department of Urology and Pediatric Urology, Saarland University, 66421 Homburg/Saar, Germany; (D.H.); (P.Z.); (H.A.); (J.H.); (M.S.)
| | - Kerstin Junker
- Department of Urology and Pediatric Urology, Saarland University, 66421 Homburg/Saar, Germany; (D.H.); (P.Z.); (H.A.); (J.H.); (M.S.)
- Correspondence:
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Targeting lactate production and efflux in prostate cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165894. [PMID: 32650130 DOI: 10.1016/j.bbadis.2020.165894] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022]
Abstract
Prostate cancer (PCa) is the most commonly diagnosed cancer in men worldwide. Screening and management of PCa remain controversial and, therefore, the discovery of novel molecular biomarkers is urgently needed. Alteration in cancer cell metabolism is a recognized hallmark of cancer, whereby cancer cells exhibit high glycolytic rates with subsequent lactate production, regardless of oxygen availability. To maintain the hyperglycolytic phenotype, cancer cells efficiently export lactate through the monocarboxylate transporters MCT1 and MCT4. The impact of inhibiting lactate production/extrusion on PCa cell survival and aggressiveness was investigated in vitro and ex vivo using primary tumor and metastatic PCa cell lines and the chicken embryo chorioallantoic membrane (CAM) model. In this study, we showed the metastatic PCa cell line (DU125) displayed higher expression levels of MCT1/4 isoforms and glycolysis-related markers than the localized prostate tumor-derived cell line (22RV1), indicating these proteins are differentially expressed throughout prostate malignant transformation. Moreover, disruption of lactate export by MCT1/4 silencing resulted in a decrease in PCa cell growth and motility. To support these results, we pharmacological inhibited lactate production (via inhibition of LDH) and release (via inhibition of MCTs) and a reduction in cancer cell growth in vitro and in vivo was observed. In summary, our data provide evidence that MCT1 and MCT4 are important players in prostate neoplastic progression and that inhibition of lactate production/export can be explored as a strategy for PCa treatment.
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Gomes SD, Oliveira CS, Azevedo-Silva J, Casanova MR, Barreto J, Pereira H, Chaves SR, Rodrigues LR, Casal M, Côrte-Real M, Baltazar F, Preto A. The Role of Diet Related Short-Chain Fatty Acids in Colorectal Cancer Metabolism and Survival: Prevention and Therapeutic Implications. Curr Med Chem 2020; 27:4087-4108. [PMID: 29848266 DOI: 10.2174/0929867325666180530102050] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 12/22/2017] [Accepted: 05/15/2018] [Indexed: 12/16/2022]
Abstract
Colorectal Cancer (CRC) is a major cause of cancer-related death worldwide. CRC increased risk has been associated with alterations in the intestinal microbiota, with decreased production of Short Chain Fatty Acids (SCFAs). SCFAs produced in the human colon are the major products of bacterial fermentation of undigested dietary fiber and starch. While colonocytes use the three major SCFAs, namely acetate, propionate and butyrate, as energy sources, transformed CRC cells primarily undergo aerobic glycolysis. Compared to normal colonocytes, CRC cells exhibit increased sensitivity to SCFAs, thus indicating they play an important role in cell homeostasis. Manipulation of SCFA levels in the intestine, through changes in microbiota, has therefore emerged as a potential preventive/therapeutic strategy for CRC. Interest in understanding SCFAs mechanism of action in CRC cells has increased in the last years. Several SCFA transporters like SMCT-1, MCT-1 and aquaporins have been identified as the main transmembrane transporters in intestinal cells. Recently, it was shown that acetate promotes plasma membrane re-localization of MCT-1 and triggers changes in the glucose metabolism. SCFAs induce apoptotic cell death in CRC cells, and further mechanisms have been discovered, including the involvement of lysosomal membrane permeabilization, associated with mitochondria dysfunction and degradation. In this review, we will discuss the current knowledge on the transport of SCFAs by CRC cells and their effects on CRC metabolism and survival. The impact of increasing SCFA production by manipulation of colon microbiota on the prevention/therapy of CRC will also be addressed.
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Affiliation(s)
- Sara Daniela Gomes
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,ICVS - Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal
| | - Cláudia Suellen Oliveira
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,ICBAS - Institute of Biomedical Sciences Abel Salazar, University of Porto, 4050-313 Porto, Portugal
| | - João Azevedo-Silva
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Marta R Casanova
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal,CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Judite Barreto
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Helena Pereira
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Susana R Chaves
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Lígia R Rodrigues
- CEB - Centre of Biological Engineering, University of Minho, Braga, Portugal
| | - Margarida Casal
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Manuela Côrte-Real
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
| | - Fátima Baltazar
- ICVS - Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal,ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Ana Preto
- CBMA - Centre of Molecular and Environmental Biology, Department of Biology, University of Minho,
Campus de Gualtar, 4710-057 Braga, Portugal
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Rodriguez JER, Garcia-Perdomo HA. Role of monocarboxylate transporters in the diagnosis, progression, prognosis, and treatment of prostate cancer. Turk J Urol 2020; 46:413-418. [PMID: 32833619 DOI: 10.5152/tud.2020.20278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 07/21/2020] [Indexed: 01/04/2023]
Abstract
Prostate cancer (PCa) is a disease with high morbidity and mortality rates, which requires finding new lines of approach. The significant advances in and interest of molecular biology in this condition have led to the discovery of elements profiled as an essential research target. Accordingly, we consider the importance of studying the role that monocarboxylate transporters (MCTs) play in PCa. These transporters might have a functional characterization, possible diagnostic and therapeutic implications, and influence on the progression and prognosis of this cancer. We reviewed literature published from January 2010 to June 2020 in different databases and search engines to find studies that respond to our question. MCTs have a close correlation with PCa, contributing to their phenotype of glycolytic and acid-resistant metabolism. They determine the maintenance and progression of the disease depending on the expression of different molecular types of the transporter. Thus, MCT2 highlights as a biomarker in early diagnosis and MCT4 in poor prognosis and resistance. Finally, MCT1 and MCT4 profile as a potential therapeutic target by decreasing cell proliferation. In conclusion, MCTs play an essential role in PCa; therefore, they should be taken into account in subsequent studies for finding tools with clinical applicability and contributing to the reduction of the disease burden.
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Affiliation(s)
| | - Herney Andrés Garcia-Perdomo
- UROGIV Research Group, Universidad del Valle, Cali, Colombia.,Department of Surgery/Urology, Universidad del Valle, School of Medicine, Cali, Colombia
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37
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Mendes C, Serpa J. Revisiting lactate dynamics in cancer—a metabolic expertise or an alternative attempt to survive? J Mol Med (Berl) 2020; 98:1397-1414. [DOI: 10.1007/s00109-020-01965-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/14/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022]
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Role of pH Regulatory Proteins and Dysregulation of pH in Prostate Cancer. Rev Physiol Biochem Pharmacol 2020; 182:85-110. [PMID: 32776252 DOI: 10.1007/112_2020_18] [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] [Indexed: 12/12/2022]
Abstract
Prostate cancer is the fourth most commonly diagnosed cancer, and although it is often a slow-growing malignancy, it is the second leading cause of cancer-associated deaths in men and the first in Europe and North America. In many forms of cancer, when the disease is a solid tumor confined to one organ, it is often readily treated. However, when the cancer becomes an invasive metastatic carcinoma, it is more often fatal. It is therefore of great interest to identify mechanisms that contribute to the invasion of cells to identify possible targets for therapy. During prostate cancer progression, the epithelial cells undergo epithelial-mesenchymal transition that is characterized by morphological changes, a loss of cell-cell adhesion, and invasiveness. Dysregulation of pH has emerged as a hallmark of cancer with a reversed pH gradient and with a constitutively increased intracellular pH that is elevated above the extracellular pH. This phenomenon has been referred to as "a perfect storm" for cancer progression. Acid-extruding ion transporters include the Na+/H+ exchanger NHE1 (SLC9A1), the Na+HCO3- cotransporter NBCn1 (SLC4A7), anion exchangers, vacuolar-type adenosine triphosphatases, and the lactate-H+ cotransporters of the monocarboxylate family (MCT1 and MCT4 (SLC16A1 and 3)). Additionally, carbonic anhydrases contribute to acid transport. Of these, several have been shown to be upregulated in different human cancers including the NBCn1, MCTs, and NHE1. Here the role and contribution of acid-extruding transporters in prostate cancer growth and metastasis were examined. These proteins make significant contributions to prostate cancer progression.
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Sun X, Wang M, Wang M, Yao L, Li X, Dong H, Li M, Sun T, Liu X, Liu Y, Xu Y. Role of Proton-Coupled Monocarboxylate Transporters in Cancer: From Metabolic Crosstalk to Therapeutic Potential. Front Cell Dev Biol 2020; 8:651. [PMID: 32766253 PMCID: PMC7379837 DOI: 10.3389/fcell.2020.00651] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 07/01/2020] [Indexed: 01/18/2023] Open
Abstract
Proton-coupled monocarboxylate transporters (MCTs), representing the first four isoforms of the SLC16A gene family, mainly participate in the transport of lactate, pyruvate, and other monocarboxylates. Cancer cells exhibit a metabolic shift from oxidative metabolism to an enhanced glycolytic phenotype, leading to a higher production of lactate in the cytoplasm. Excessive accumulation of lactate threatens the survival of cancer cells, and the overexpression of proton-coupled MCTs observed in multiple types of cancer facilitates enhanced export of lactate from highly glycolytic cancer cells. Proton-coupled MCTs not only play critical roles in the metabolic symbiosis between hypoxic and normoxic cancer cells within tumors but also mediate metabolic interaction between cancer cells and cancer-associated stromal cells. Of the four proton-coupled MCTs, MCT1 and MCT4 are the predominantly expressed isoforms in cancer and have been identified as potential therapeutic targets in cancer. Therefore, in this review, we primarily focus on the roles of MCT1 and MCT4 in the metabolic reprogramming of cancer cells under hypoxic and nutrient-deprived conditions. Additionally, we discuss how MCT1 and MCT4 serve as metabolic links between cancer cells and cancer-associated stromal cells via transport of crucial monocarboxylates, as well as present emerging opportunities and challenges in targeting MCT1 and MCT4 for cancer treatment.
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Affiliation(s)
- Xiangyu Sun
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mozhi Wang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mengshen Wang
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Litong Yao
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xinyan Li
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Haoran Dong
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Meng Li
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Tie Sun
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xing Liu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yang Liu
- The Second Affiliated Hospital of China Medical University, Shenyang, China
| | - Yingying Xu
- Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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40
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Guan X, Morris ME. In Vitro and In Vivo Efficacy of AZD3965 and Alpha-Cyano-4-Hydroxycinnamic Acid in the Murine 4T1 Breast Tumor Model. AAPS JOURNAL 2020; 22:84. [PMID: 32529599 DOI: 10.1208/s12248-020-00466-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 05/19/2020] [Indexed: 01/11/2023]
Abstract
Monocarboxylate transporter 1 (MCT1) represents a potential therapeutic target in cancer. The objective of this study was to determine the efficacy of AZD3965 (a specific inhibitor of MCT1) and α-cyano-4-hydroxycinnamic acid (CHC, a nonspecific inhibitor of MCTs) in the murine 4T1 tumor model of triple-negative breast cancer (TNBC). Expression of MCT1 and MCT4 in 4T1 and mouse mammary epithelial cells were determined by Western blot. Inhibition of MCT1-mediated L-lactate uptake and cellular proliferation by AZD3965 and CHC was determined. Mice bearing 4T1 breast tumors were treated with AZD3965 100 mg/kg i.p. twice-daily or CHC 200 mg/kg i.p. once-daily. Tumor growth, metastasis, intra-tumor lactate concentration, immune function, tumor MCT expression, and concentration-effect relationships were determined. AZD3965 and CHC inhibited cell growth and L-lactate uptake in 4T1 cells. AZD3965 treatment resulted in trough plasma and tumor concentrations of 29.1 ± 13.9 and 1670 ± 946 nM, respectively. AZD3965 decreased the tumor proliferation biomarker Ki67 expression, increased intra-tumor lactate concentration, and decreased tumor volume, although tumor weight was not different from untreated controls. CHC had no effect on tumor volume and weight, or intra-tumor lactate concentration. AZD3965 treatment reduced the blood leukocyte count and spleen weight and increased lung metastasis, while CHC did not. These findings indicate AZD3965 is a potent MCT1 inhibitor that accumulates to high concentrations in 4T1 xenograft tumors, where it increases tumor lactate concentrations and produces beneficial effects on markers of TNBC; however, overall effects on tumor growth were minimal and lung metastases increased.
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Affiliation(s)
- Xiaowen Guan
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 304 Pharmacy Building, Buffalo, New York, 14214, USA.,Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Redwood City, California, 94063, USA
| | - Marilyn E Morris
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 304 Pharmacy Building, Buffalo, New York, 14214, USA.
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41
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Puri S, Juvale K. Monocarboxylate transporter 1 and 4 inhibitors as potential therapeutics for treating solid tumours: A review with structure-activity relationship insights. Eur J Med Chem 2020; 199:112393. [PMID: 32388280 DOI: 10.1016/j.ejmech.2020.112393] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023]
Abstract
Development of multidrug resistance (MDR) is one of the major causes leading to failure of cancer chemotherapy and radiotherapy. Monocarboxylate transporters (MCTs) MCT1 and MCT4, which are overexpressed in solid tumours, play a very important role in cancer cell survival and proliferation. These lactate transporters work complimentarily to drive lactate shuttle in tumour cells, which results in maintenance of H+ ion (pH) balance necessary for their survival. Inhibition of these transmembrane proteins has been demonstrated as a novel strategy to treat drug resistant solid cancers. Presently, only a few small molecule MCT1 inhibitors such as AZD3965 and AR-C155858 are known with clinical potential. Even lesser mention of MCT4 inhibitors, which include molecules having scaffolds such as pyrazole and indazole, is available in the literature. Current overview presents the status of recent developments undertaken in identification of efficacious MCT1 and/or MCT4 inhibitors as a potential anticancer therapy overcoming MDR. Further, detailed structure-activity relationships for different classes of compounds has been proposed to streamline the understandings learnt from ongoing research work. Through this review, we aim to highlight the importance of these excellent targets and facilitate future development of selective, potent and safe MCT1 and/or MCT4 inhibitors as promising chemotherapy for drug resistant cancer.
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Affiliation(s)
- Sachin Puri
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India
| | - Kapil Juvale
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India.
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42
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Ward C, Meehan J, Gray ME, Murray AF, Argyle DJ, Kunkler IH, Langdon SP. The impact of tumour pH on cancer progression: strategies for clinical intervention. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:71-100. [PMID: 36046070 PMCID: PMC9400736 DOI: 10.37349/etat.2020.00005] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/05/2020] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H+-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets.
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Affiliation(s)
- Carol Ward
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - James Meehan
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Mark E Gray
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG Midlothian, UK
| | - Alan F Murray
- School of Engineering, Institute for Integrated Micro and Nano Systems, EH9 3JL Edinburgh, UK
| | - David J Argyle
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG Midlothian, UK
| | - Ian H Kunkler
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Simon P Langdon
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
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Baltazar F, Afonso J, Costa M, Granja S. Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy. Front Oncol 2020; 10:231. [PMID: 32257942 PMCID: PMC7093491 DOI: 10.3389/fonc.2020.00231] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 02/11/2020] [Indexed: 12/16/2022] Open
Abstract
To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.
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Affiliation(s)
- Fátima Baltazar
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
| | - Julieta Afonso
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
| | - Marta Costa
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
| | - Sara Granja
- School of Medicine, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal
- ICVS/3B's—PT Government Associate Laboratory, Guimarães, Portugal
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Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures. Cancers (Basel) 2020; 12:cancers12030537. [PMID: 32110965 PMCID: PMC7139946 DOI: 10.3390/cancers12030537] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 02/23/2020] [Accepted: 02/24/2020] [Indexed: 12/11/2022] Open
Abstract
Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR.
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One-step radiosynthesis of the MCTs imaging agent [ 18F]FACH by aliphatic 18F-labelling of a methylsulfonate precursor containing an unprotected carboxylic acid group. Sci Rep 2019; 9:18890. [PMID: 31827199 PMCID: PMC6906299 DOI: 10.1038/s41598-019-55354-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023] Open
Abstract
Monocarboxylate transporters 1 and 4 (MCT1 and MCT4) are involved in tumour development and progression. Their level of expression is particularly upregulated in glycolytic cancer cells and accordingly MCTs are considered as promising drug targets for treatment of a variety of human cancers. The non-invasive imaging of these transporters in cancer patients via positron emission tomography (PET) is regarded to be valuable for the monitoring of therapeutic effects of MCT inhibitors. Recently, we developed the first 18F-radiolabelled MCT1/MCT4 inhibitor [18F]FACH and reported on a two-step one-pot radiosynthesis procedure. We herein describe now a unique one-step radiosynthesis of this radiotracer which is based on the approach of using a methylsulfonate (mesylate) precursor bearing an unprotected carboxylic acid function. With the new procedure unexpected high radiochemical yields of 43 ± 8% at the end of the radiosynthesis could be obtained in a strongly reduced total synthesis time. Moreover, the radiosynthesis was successfully transferred to a TRACERlab FX2 N synthesis module ready for future preclinical applications of [18F]FACH.
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Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther 2019; 206:107451. [PMID: 31836453 DOI: 10.1016/j.pharmthera.2019.107451] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/22/2019] [Indexed: 12/15/2022]
Abstract
Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics.
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Affiliation(s)
- Timothy P Brown
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Vadivel Ganapathy
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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Cai T, Zhang C, Zeng X, Zhao Z, Yan Y, Yu X, Wu L, Lin L, Pan H. Protective effects of Weipixiao decoction against MNNG-induced gastric precancerous lesions in rats. Biomed Pharmacother 2019; 120:109427. [PMID: 31648165 DOI: 10.1016/j.biopha.2019.109427] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/29/2019] [Accepted: 09/02/2019] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer is recognized as one of the most common cancer. In-depth research of gastric precancerous lesions (GPL) plays an important role in preventing the occurrence of gastric cancer. Meanwhile, traditional treatment provides a novel sight in the prevention of occurrence and development of gastric cancer. The current study was designed to assess the effects of therapy with Weipixiao (WPX) decoction on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL rats and the underlying molecular mechanisms. After 10-weeks treatment, all rats were sacrificed. Histopathological changes of gastric tissue were assessed via hematoxylin-eosin (HE) and High-iron diamine-Alcian blue-Periodic acid-Schiff (HID-AB-PAS) staining. To be fully evidenced, RT-qPCR, Western blot and immunohistochemistry were used to detect the expressions of LDHA, CD147, HIF-1α, MCT4, PI3K, AKT, mTOR and miRNA-34a, which were crucial factors for evaluating GPL in the aspect of glycolysis pathogenesis. According to the results of HE and HID-AB-PAS staining, it could be confirmed that MNNG-induced GPL rats were obviously reversed by WPX decoction. Additionally, the increased gene levels of LDHA, CD147, MCT4, PI3K, AKT, mTOR and HIF-1α in model group were down-regulated by WPX decoction, while miRNA-34a expression was decreased and up-regulated by WPX decoction. The significantly increased protein levels of LDHA, CD147, MCT4, PI3K, AKT, mTOR and HIF-1α induced by MNNG were attenuated in rats treated with WPX decoction. In brief, the findings of this study imply that abnormal glycolysis in MNNG-induced GPL rats was relieved by WPX decoction via regulation of the expressions of LDHA, CD147, HIF-1α, MCT4, PI3K, AKT, mTOR and miRNA-34a.
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Affiliation(s)
- Tiantian Cai
- Guangzhou University of Chinese Medicine, Guangzhou, Guanghdong, 510000, China; Department of Respiratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou,Guanghdong, 510000, China
| | - Chengzhe Zhang
- Guangzhou University of Chinese Medicine, Guangzhou, Guanghdong, 510000, China; Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guanghdong, 510000, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guanghdong, 510000, China
| | - Xiaohui Zeng
- Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guanghdong, 510000, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guanghdong, 510000, China
| | - Ziming Zhao
- Guangdong Province Engineering Technology Research Institute of Traditional Chinese Medicine, Guangzhou, Guanghdong, 510000, China; Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou, Guanghdong, 510000, China
| | - Yan Yan
- Guangzhou University of Chinese Medicine, Guangzhou, Guanghdong, 510000, China
| | - Xuhua Yu
- Department of Respiratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou,Guanghdong, 510000, China; Department of Respiratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou,Guanghdong, 510000, China
| | - Lei Wu
- Department of Respiratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou,Guanghdong, 510000, China; Department of Respiratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou,Guanghdong, 510000, China
| | - Lin Lin
- Department of Respiratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou,Guanghdong, 510000, China; Department of Respiratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou,Guanghdong, 510000, China.
| | - Huafeng Pan
- Guangzhou University of Chinese Medicine, Guangzhou, Guanghdong, 510000, China.
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Schobert I, Chapiro J, Pucar D, Saperstein L, Savic LJ. Fluorodeoxyglucose PET for Monitoring Response to Embolotherapy (Transarterial Chemoembolization) in Primary and Metastatic Liver Tumors. PET Clin 2019; 14:437-445. [DOI: 10.1016/j.cpet.2019.06.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Silva GR, Vaz CV, Catalão B, Ferreira S, Cardoso HJ, Duarte AP, Socorro S. Sweet Cherry Extract Targets the Hallmarks of Cancer in Prostate Cells: Diminished Viability, Increased Apoptosis and Suppressed Glycolytic Metabolism. Nutr Cancer 2019; 72:917-931. [PMID: 31507215 DOI: 10.1080/01635581.2019.1661502] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The present work evaluated the anticancer properties of sweet cherry (Prunus avium) extract on human prostate cells. Several sweet cherry cultivars from Fundão (Portugal) were methanol-extracted and their phytochemical composition characterized. The Saco "late harvest" extract was highly-enriched in anthocyanins and selected for use in biological assays. Non-neoplastic (PNT1A) and neoplastic (LNCaP and PC3) human prostate cells were treated with 0-2,000 μg/ml of extract for 48-96 h. Cell viability was evaluated by the MTT assay. Apoptosis, oxidative stress, and glycolytic metabolism were assessed by Western blotting and enzymatic assays. Glucose consumption and lactate production were measured spectrophotometrically. Saco cherry extract diminished the viability of neoplastic and non-neoplastic cells, whereas enhancing apoptosis in LNCaP. Cherry extract-treatment also diminished oxidative damage and suppressed glycolytic metabolism in LNCaP cells. These findings widened the knowledge on the mechanisms by which cherry extract modulate cell physiology, demonstrating their broad action over the hallmarks of cancer.
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Affiliation(s)
- Gonçalo R Silva
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Cátia V Vaz
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Beatriz Catalão
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Susana Ferreira
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Henrique J Cardoso
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Ana Paula Duarte
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Sílvia Socorro
- CICS-UBI - Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
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