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Zhang T, Zhou W, Fan T, Yuan Y, Tang X, Zhang Q, Zou J, Li Y. Lactic acid metabolism: gynecological cancer's Achilles' heel. Discov Oncol 2025; 16:657. [PMID: 40314877 PMCID: PMC12048388 DOI: 10.1007/s12672-025-02364-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 04/10/2025] [Indexed: 05/03/2025] Open
Abstract
Lactic acid is significantly expressed in many cancers, including gynecological cancer, and has become a key regulator of the proliferation, development, metastasis and invasion of these cancers. In clinical and experimental studies, the level of lactic acid in gynecological cancer is closely related to metastasis and invasion, tumor recurrence and poor prognosis. Lactic acid can regulate the internal metabolic pathway of gynecological cancer cells and drive the autonomous role of non-cancer cells in gynecological cancer. In addition to being used as a source of energy metabolism by gynecological cancer cells, lactic acid can also be transported from cancer cells to neighboring cancer cells, stroma and vascular endothelial cells (ECs) to further guide metabolic reprogramming. Lactic acid is also involved in promoting inflammation and angiogenesis in gynecologic tumors. Therefore, we reviewed the mechanisms and recent advances in the production and transport of lactic acid in gynecological cancer. These advances and evidence suggest that targeted lactic acid metabolism is a promising cancer treatment.
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Affiliation(s)
- Ting Zhang
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China
| | - Wenchao Zhou
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China
| | - Tingyu Fan
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China
- Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China
| | - Yuwei Yuan
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China
| | - Xing Tang
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China
- Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China
| | - Qunfeng Zhang
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China.
- Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China.
| | - Juan Zou
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China.
- Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China.
| | - Yukun Li
- The Second Affiliated Hospital, Department of Gynecology, Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Hengyang Medical School, Cancer Research Institute, University of South China, Hengyang, Hunan, China.
- Department of Assisted Reproductive Centre, Zhuzhou Central Hospital, Xiangya Hospital Zhuzhou Central South University, Central South University, Zhuzhou, Hunan, China.
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Combs JE, Murray AB, Lomelino CL, Mboge MY, Mietzsch M, Horenstein NA, Frost SC, McKenna R, Becker HM. Disruption of the Physical Interaction Between Carbonic Anhydrase IX and the Monocarboxylate Transporter 4 Impacts Lactate Transport in Breast Cancer Cells. Int J Mol Sci 2024; 25:11994. [PMID: 39596062 PMCID: PMC11593560 DOI: 10.3390/ijms252211994] [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: 10/10/2024] [Revised: 11/02/2024] [Accepted: 11/06/2024] [Indexed: 11/28/2024] Open
Abstract
It has been previously established that breast cancer cells exhibit high expression of the monocarboxylate (lactate) transporters (MCT1 and/or MCT4) and carbonic anhydrase IX (CAIX) and form a functional metabolon for proton-coupled lactate export, thereby stabilizing intracellular pH. CD147 is the MCT accessory protein that facilitates the creation of the MCT/CAIX complex. This study describes how the small molecule Beta-Galactose 2C (BGal2C) blocks the physical and functional interaction between CAIX and either MCT1 or MCT4 in Xenopus oocytes, which reduces the rate of proton and lactate flux with an IC50 of ~90 nM. This value is similar to the Ki for inhibition of CAIX activity. Furthermore, it is shown that BGal2C blocks hypoxia-induced lactate transport in MDA-MB-231 and MCF-7 breast cancer cells, both of which express CAIX. As in oocytes, BGal2C interferes with the physical interaction between CAIX and MCTs in both cell types. Finally, X-ray crystallographic studies highlight unique interactions between BGal2C and a CAIX-mimic that are not observed within the CAII active site and which may underlie the strong specificity of BGal2C for CAIX. These studies demonstrate the utility of a novel sulfonamide in interfering with elevated proton and lactate flux, a hallmark of many solid tumors.
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Affiliation(s)
- Jacob E. Combs
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | - Akilah B. Murray
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | - Carrie L. Lomelino
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | - Mam Y. Mboge
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | - Mario Mietzsch
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | | | - Susan C. Frost
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | - Robert McKenna
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32611, USA (M.M.); (S.C.F.)
| | - Holger M. Becker
- Institute of Physiological Chemistry, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, 30625 Hannover, Germany
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3
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Littleflower AB, Parambil ST, Antony GR, Subhadradevi L. The determinants of metabolic discrepancies in aerobic glycolysis: Providing potential targets for breast cancer treatment. Biochimie 2024; 220:107-121. [PMID: 38184121 DOI: 10.1016/j.biochi.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 12/22/2023] [Accepted: 01/03/2024] [Indexed: 01/08/2024]
Abstract
Altered aerobic glycolysis is the robust mechanism to support cancer cell survival and proliferation beyond the maintenance of cellular energy metabolism. Several investigators portrayed the important role of deregulated glycolysis in different cancers, including breast cancer. Breast cancer is the most ubiquitous form of cancer and the primary cause of cancer death in women worldwide. Breast cancer with increased glycolytic flux is hampered to eradicate with current therapies and can result in tumor recurrence. In spite of the low order efficiency of ATP production, cancer cells are highly addicted to glycolysis. The glycolytic dependency of cancer cells provides potential therapeutic strategies to preferentially kill cancer cells by inhibiting glycolysis using antiglycolytic agents. The present review emphasizes the most recent research on the implication of glycolytic enzymes, including glucose transporters (GLUTs), hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), lactate dehydrogenase-A (LDHA), associated signalling pathways and transcription factors, as well as the antiglycolytic agents that target key glycolytic enzymes in breast cancer. The potential activity of glycolytic inhibitors impinges cancer prevalence and cellular resistance to conventional drugs even under worse physiological conditions such as hypoxia. As a single agent or in combination with other chemotherapeutic drugs, it provides the feasibility of new therapeutic modalities against a wide spectrum of human cancers.
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Affiliation(s)
- Ajeesh Babu Littleflower
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Sulfath Thottungal Parambil
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Gisha Rose Antony
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India
| | - Lakshmi Subhadradevi
- Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, Kerala, 695011, India.
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4
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Zhao J, Sun H, Wang C, Shang D. Breast cancer therapy: from the perspective of glucose metabolism and glycosylation. Mol Biol Rep 2024; 51:546. [PMID: 38642246 DOI: 10.1007/s11033-024-09466-w] [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: 02/12/2024] [Accepted: 03/22/2024] [Indexed: 04/22/2024]
Abstract
Breast cancer is a leading cause of mortality and the most prevalent form of malignant tumor among women worldwide. Breast cancer cells exhibit an elevated glycolysis and altered glucose metabolism. Moreover, these cells display abnormal glycosylation patterns, influencing invasion, proliferation, metastasis, and drug resistance. Consequently, targeting glycolysis and mitigating abnormal glycosylation represent key therapeutic strategies for breast cancer. This review underscores the importance of protein glycosylation and glucose metabolism alterations in breast cancer. The current research efforts in developing effective interventions targeting glycolysis and glycosylation are further discussed.
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Affiliation(s)
- Jiaqi Zhao
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Haiting Sun
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China
| | - Che Wang
- Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, 116029, China.
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
| | - Dejing Shang
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, 116081, China.
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Sung JS, Han Y, Yun TG, Jung J, Kim TH, Piccinini F, Kang MJ, Jose J, Lee M, Pyun JC. Monocarboxylate transporter-1 (MCT-1) inhibitors screened from autodisplayed F V-antibody library. Int J Biol Macromol 2024; 265:130854. [PMID: 38484814 DOI: 10.1016/j.ijbiomac.2024.130854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/10/2024] [Accepted: 03/11/2024] [Indexed: 03/25/2024]
Abstract
Monocarboxylate transporter-1 (MCT-1) inhibitors were screened from the Fv-antibody library, which contained complementary determining region 3 with randomized amino acid sequences (11 residues) through site-directed mutagenesis. Fv-antibodies against MCT-1 were screened from the autodisplayed Fv-antibody library. Two clones were screened, and the binding affinity (KD) against MCT-1 was estimated using flow cytometry. The screened Fv-antibodies were expressed as soluble fusion proteins (Fv-1 and Fv-2) and the KD for MCT-1 was estimated using the SPR biosensor. The inhibitory activity of the expressed Fv-antibodies was observed in HEK293T and Jurkat cell lines by measuring intracellular pH and lactate accumulation. The level of cell viability in HEK293T and Jurkat cell lines was decreased by the inhibitory activity of the expressed Fv-antibodies. The binding properties of the Fv-antibodies to MCT-1 were analyzed using molecular docking simulations. Overall, the results showed that the screened Fv-antibodies against MCT-1 from the Fv-antibody library had high binding affinity and inhibitory activity against MCT-1, which could be used as potential therapeutic drug candidates for the MCT-1 inhibitor.
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Affiliation(s)
- Jeong Soo Sung
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea
| | - Yeonju Han
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea
| | - Tae Gyeong Yun
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea
| | - Jaeyong Jung
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea
| | - Tae-Hun Kim
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea
| | - Filippo Piccinini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy; IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Min-Jung Kang
- Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
| | - Joachim Jose
- Institute of Pharmaceutical and Medical Chemistry, Westfälischen Wilhelms-Universität Münster, Muenster, Germany
| | - Misu Lee
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea; Institute for New Drug Development, College of Life Science and Bioengineering, Incheon National University, South Korea
| | - Jae-Chul Pyun
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Republic of Korea.
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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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7
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Kim NI, Park MH, Kweon SS, Lee JS. Metabolic coupling in phyllodes tumor of the breast and its association with tumor progression. Oncol Lett 2023; 26:545. [PMID: 38020291 PMCID: PMC10660424 DOI: 10.3892/ol.2023.14132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 10/13/2023] [Indexed: 12/01/2023] Open
Abstract
There are markers of metabolic coupling in breast cancer. Loss of caveolin-1 (Cav-1) and upregulation of monocarboxylate transporters (MCTs), especially MCT1 and MCT4, serve an important role in metabolic coupling necessary for release and uptake of metabolites. However, the occurrence of these phenomena in phyllodes tumors (PTs) of the breast is unclear. A total of 101 PTs (60 benign, 26 borderline and 15 malignant) and nine breast tissue samples with no pathological lesions were analyzed. Immunohistochemical staining for Cav-1, MCT1 and MCT4 was performed using tissue microarray and their expression in both stromal and epithelial components was assessed. Cav-1 expression in PTs demonstrated a significant decrease in the stromal component compared with that in the normal breast tissues (P<0.001). MCT1 expression in both epithelial and stromal components was significantly increased in PTs, compared with that in normal breast tissues (both P<0.001). Stromal MCT1 and MCT4 expression were different depending on tumor grade of PTs, and stromal MCT1 expression significantly increased with increasing tumor grade (P<0.001). Although not statistically significant, stromal Cav-1 expression notably decreased with increases in PT grade. High stromal MCT1 expression was significantly associated with lower disease-free survival rate in comparison with low stromal MCT1 expression (P<0.05). These results suggested that changes in protein expression of Cav-1, MCT1 and MCT4 may be associated with tumorigenesis and progression of PTs of the breast.
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Affiliation(s)
- Nah Ihm Kim
- Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Min Ho Park
- Department of Surgery, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Ji Shin Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
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8
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Frisardi V, Canovi S, Vaccaro S, Frazzi R. The Significance of Microenvironmental and Circulating Lactate in Breast Cancer. Int J Mol Sci 2023; 24:15369. [PMID: 37895048 PMCID: PMC10607673 DOI: 10.3390/ijms242015369] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/09/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Lactate represents the main product of pyruvate reduction catalyzed by the lactic dehydrogenase family of enzymes. Cancer cells utilize great quantities of glucose, shifting toward a glycolytic metabolism. With the contribution of tumor stromal cells and under hypoxic conditions, this leads toward the acidification of the extracellular matrix. The ability to shift between different metabolic pathways is a characteristic of breast cancer cells and is associated with an aggressive phenotype. Furthermore, the preliminary scientific evidence concerning the levels of circulating lactate in breast cancer points toward a correlation between hyperlactacidemia and poor prognosis, even though no clear linkage has been demonstrated. Overall, lactate may represent a promising metabolic target that needs to be investigated in breast cancer.
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Affiliation(s)
- Vincenza Frisardi
- Geriatric Unit, Neuromotor Department, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
| | - Simone Canovi
- Clinical Laboratory, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
| | - Salvatore Vaccaro
- Clinical Nutrition Unit and Oncological Metabolic Centre, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
| | - Raffaele Frazzi
- Scientific Directorate, Azienda Unità Sanitaria Locale—IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy
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9
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Singh M, Afonso J, Sharma D, Gupta R, Kumar V, Rani R, Baltazar F, Kumar V. Targeting monocarboxylate transporters (MCTs) in cancer: How close are we to the clinics? Semin Cancer Biol 2023; 90:1-14. [PMID: 36706846 DOI: 10.1016/j.semcancer.2023.01.007] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/23/2023] [Accepted: 01/23/2023] [Indexed: 01/26/2023]
Abstract
As a result of metabolic reprogramming, cancer cells display high rates of glycolysis, causing an excess production of lactate along with an increase in extracellular acidity. Proton-linked monocarboxylate transporters (MCTs) are crucial in the maintenance of this metabolic phenotype, by mediating the proton-coupled lactate flux across cell membranes, also contributing to cancer cell pH regulation. Among the proteins codified by the SLC16 gene family, MCT1 and MCT4 isoforms are the most explored in cancers, being overexpressed in many cancer types, from solid tumours to haematological malignancies. Similarly to what occurs in particular physiological settings, MCT1 and MCT4 are able to mediate lactate shuttles among cancer cells, and also between cancer and stromal cells in the tumour microenvironment. This form of metabolic cooperation is responsible for important cancer aggressiveness features, such as cell proliferation, survival, angiogenesis, migration, invasion, metastasis, immune tolerance and therapy resistance. The growing understanding of MCT functions and regulation is offering a new path to the design of novel inhibitors that can be foreseen in clinical practices. This review provides an overview of the role of MCT isoforms in cancer and summarizes the recent advances in their pharmacological targeting, highlighting the potential of new potent and selective MCT1 and/or MCT4 inhibitors in cancer therapeutics, and anticipating its inclusion in clinical practice.
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Affiliation(s)
- Mamta Singh
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India
| | - Julieta Afonso
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal
| | - Dolly Sharma
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India; Amity Institute of Biotechnology, Amity University UP, Sector-125, Noida, India-201313
| | - Rajat Gupta
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India
| | - Vivek Kumar
- Department of Chemistry, DBG College, Sector-18, Panipat, Haryana, India
| | - Reshma Rani
- Drug Discovery, Jubilant Biosys, Greater Noida 201306, UP, India.
| | - Fátima Baltazar
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Guimarães, Portugal.
| | - Vinit Kumar
- Amity Institute of Molecular Medicine and Stem Cell Research Amity, University UP, Sector-125, Noida 201313, India.
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10
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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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Alizadeh J, Kavoosi M, Singh N, Lorzadeh S, Ravandi A, Kidane B, Ahmed N, Mraiche F, Mowat MR, Ghavami S. Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer. Cancers (Basel) 2023; 15:2195. [PMID: 37190124 PMCID: PMC10136996 DOI: 10.3390/cancers15082195] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/21/2023] [Accepted: 03/28/2023] [Indexed: 05/17/2023] Open
Abstract
Metabolic changes are an important component of tumor cell progression. Tumor cells adapt to environmental stresses via changes to carbohydrate and lipid metabolism. Autophagy, a physiological process in mammalian cells that digests damaged organelles and misfolded proteins via lysosomal degradation, is closely associated with metabolism in mammalian cells, acting as a meter of cellular ATP levels. In this review, we discuss the changes in glycolytic and lipid biosynthetic pathways in mammalian cells and their impact on carcinogenesis via the autophagy pathway. In addition, we discuss the impact of these metabolic pathways on autophagy in lung cancer.
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Affiliation(s)
- Javad Alizadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Mahboubeh Kavoosi
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Navjit Singh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Shahrokh Lorzadeh
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
| | - Amir Ravandi
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Institute of Cardiovascular Sciences, Albrechtsen Research Centre, St. Boniface Hospital, Winnipeg, MB R2H 2A6, Canada;
| | - Biniam Kidane
- Section of Thoracic Surgery, Department of Surgery, Health Sciences Centre, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 6C5, Canada;
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
| | - Naseer Ahmed
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
- Department of Radiology, Section of Radiation Oncology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Fatima Mraiche
- College of Pharmacy, QU Health, Qatar University, Doha 2713, Qatar;
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Michael R. Mowat
- CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada; (N.A.)
- Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, MB R3E 0V9, Canada (S.L.)
- Research Institute of Oncology and Hematology, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine in Zabrze, Academia of Silesia, 41-800 Zabrze, Poland
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada
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12
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Kim NI, Park MH, Lee JS. Expression of Cav-1, MCT1, and MCT4 in Ductal Carcinoma In Situ of the Breast and Their Associations With Clinicopathologic Features. Appl Immunohistochem Mol Morphol 2023; 31:204-212. [PMID: 36867736 DOI: 10.1097/pai.0000000000001106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/10/2023] [Indexed: 03/05/2023]
Abstract
Loss of caveolin-1 (Cav-1) and upregulation of monocarboxylate transporters (MCTs, especially MCT1 and MCT4) in respectively tumor-associated stromal cells and malignant epithelial cells of invasive carcinoma have been found to play an important role in the metabolic coupling. However, this phenomenon has only been scarcely described in pure ductal carcinoma in situ (DCIS) of the breast. mRNA and protein expression levels of Cav-1, MCT1, and MCT4 in nine pairs of DCIS tissues and matched normal tissues were examined by quantitative real-time polymerase chain reaction, RNAscope in situ hybridization, and immunohistochemistry. Immunohistochemical staining of Cav-1, MCT1, and MCT4 in 79 DCIS samples was also done using tissue microarray. Cav-1 mRNA expression was significantly lower in DCIS tissues than in their corresponding normal tissues. In contrast, MCT1 and MCT4 mRNA expression levels were higher in DCIS tissues than in corresponding normal tissues. Low stromal Cav-1 expression was significantly associated with high nuclear grade. High epithelial MCT4 expression was associated with larger tumor size and human epidermal growth factor 2 positivity. At a mean follow-up of 10 years, patients with high epithelial MCT1/high epithelial MCT4 expression showed shorter disease-free survival than those with other expressions. No significant association was observed between stromal Cav-1 expression and epithelial MCT 1 or MCT4 expression. Changes in Cav-1, MCT1, and MCT4 are associated with carcinogenesis of DCIS. A high epithelial MCT1/high epithelial MCT4 expression might be associated with a more aggressive phenotype.
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Affiliation(s)
| | - Min Ho Park
- Surgery, Chonnam National University Medical School, Gwangju, South Korea
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13
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Caligiuri I, Vincenzo C, Asano T, Kumar V, Rizzolio F. The metabolic crosstalk between PIN1 and the tumour microenvironment. Semin Cancer Biol 2023; 91:143-157. [PMID: 36871635 DOI: 10.1016/j.semcancer.2023.03.001] [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: 09/12/2022] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/06/2023]
Abstract
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is a member of a family of peptidyl-prolyl isomerases that specifically recognizes and binds phosphoproteins, catalyzing the rapid cis-trans isomerization of phosphorylated serine/threonine-proline motifs, which leads to changes in the structures and activities of the targeted proteins. Through this complex mechanism, PIN1 regulates many hallmarks of cancer including cell autonomous metabolism and the crosstalk with the cellular microenvironment. Many studies showed that PIN1 is largely overexpressed in cancer turning on a set of oncogenes and abrogating the function of tumor suppressor genes. Among these targets, recent evidence demonstrated that PIN1 is involved in lipid and glucose metabolism and accordingly, in the Warburg effect, a characteristic of tumor cells. As an orchestra master, PIN1 finely tunes the signaling pathways allowing cancer cells to adapt and take advantage from a poorly organized tumor microenvironment. In this review, we highlight the trilogy among PIN1, the tumor microenvironment and the metabolic program rewiring.
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Affiliation(s)
- Isabella Caligiuri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Canzonieri Vincenzo
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Tomochiro Asano
- Department of Medical Science, Graduate School of Medicine, Hiroshima University, Hiroshima 734-8553, Japan
| | - Vinit Kumar
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India.
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30123 Venezia, Italy.
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14
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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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15
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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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16
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Shum HCE, Wu K, Vadgama J, Wu Y. Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer. J Pers Med 2023; 13:157. [PMID: 36675817 PMCID: PMC9861470 DOI: 10.3390/jpm13010157] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/08/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed.
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Affiliation(s)
- Hang Chee Erin Shum
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ke Wu
- David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1748 E. 118th Street, Los Angeles, CA 90095, USA
| | - Jaydutt Vadgama
- David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1748 E. 118th Street, Los Angeles, CA 90095, USA
| | - Yong Wu
- David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, 1748 E. 118th Street, Los Angeles, CA 90095, USA
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17
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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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18
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A combination of novel NSC small molecule inhibitor along with doxorubicin inhibits proliferation of triple-negative breast cancer through metabolic reprogramming. Oncogene 2022; 41:5076-5091. [PMID: 36243802 DOI: 10.1038/s41388-022-02497-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/27/2022] [Accepted: 09/30/2022] [Indexed: 11/09/2022]
Abstract
Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and the highly invasive and proliferative nature of TNBC cells. Current treatments against TNBC have shown little promise due to high recurrence rate in patients. Consequently, there is a pressing need for novel and efficacious therapies against TNBC. Here, we report the discovery of a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. The anti-proliferative effects of this small molecule inhibitor were determined using 2D and 3D cell proliferation assays. We found that NSC33353 significantly reduces the proliferation of TNBC cells in these assays. Using proteomics, next generation sequencing (NGS), and gene enrichment analysis, we investigated global regulatory pathways affected by this compound in TNBC cells. Proteomics data indicate a significant metabolic reprograming affecting both glycolytic enzymes and energy generation through oxidative phosphorylation. Subsequently, using metabolic (Seahorse) and enzymatic assays, we validated our proteomics and NGS analysis findings. Finally, we showed the inhibitory and anti-tumor effects of this small molecule in vitro and confirmed its inhibitory activity in vivo. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug has been a major problem. We show that the combination of NSC33353 and doxorubicin suppresses the growth of TNBC cells synergistically, suggesting that NSC33353 enhances TNBC sensitivity to doxorubicin. In summary, our data indicate that the small molecule inhibitor, NSC33353, exhibits anti-tumor activity in TNBC cells, and works in a synergistic fashion with a well-known chemotherapeutic agent.
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19
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Poddar A, Rao SR, Prithviraj P, Kannourakis G, Jayachandran A. Crosstalk between Immune Checkpoint Modulators, Metabolic Reprogramming and Cellular Plasticity in Triple-Negative Breast Cancer. Curr Oncol 2022; 29:6847-6863. [PMID: 36290817 PMCID: PMC9601266 DOI: 10.3390/curroncol29100540] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 01/13/2023] Open
Abstract
Breast cancer is one of the major causes of mortality in women worldwide. Accounting for 15-20% of all breast cancer diagnoses, the triple-negative breast cancer (TNBC) subtype presents with an aggressive clinical course, heightened metastatic potential and the poorest short-term prognosis. TNBC does not respond to hormonal therapy, only partially responds to radio- and chemotherapy, and has limited targeted therapy options, thus underlining the critical need for better therapeutic treatments. Although immunotherapy based on immune checkpoint inhibition is emerging as a promising treatment option for TNBC patients, activation of cellular plasticity programs such as metabolic reprogramming (MR) and epithelial-to-mesenchymal transition (EMT) causes immunotherapy to fail. In this report, we review the role of MR and EMT in immune checkpoint dysregulation in TNBCs and specifically shed light on development of novel combination treatment modalities for this challenging disease. We highlight the clinical relevance of crosstalk between MR, EMT, and immune checkpoints in TNBCs.
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Affiliation(s)
- Arpita Poddar
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- Department of Materials Science and Engineering, Monash University, Melbourne, VIC 3800, Australia
- Ian Potter NanoBiosensing Facility, NanoBiotechnology Research Laboratory (NBRL), School of Science, RMIT University, Melbourne, VIC 3000, Australia
| | - Sushma R. Rao
- Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia
| | - Prashanth Prithviraj
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- School of Science, Psychology and Sports, Federation University Australia, Ballarat, VIC 3350, Australia
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- School of Science, Psychology and Sports, Federation University Australia, Ballarat, VIC 3350, Australia
| | - Aparna Jayachandran
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia
- School of Science, Psychology and Sports, Federation University Australia, Ballarat, VIC 3350, Australia
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD 4120, Australia
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20
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Lv L, Yang S, Zhu Y, Zhai X, Li S, Tao X, Dong D. Relationship between metabolic reprogramming and drug resistance in breast cancer. Front Oncol 2022; 12:942064. [PMID: 36059650 PMCID: PMC9434120 DOI: 10.3389/fonc.2022.942064] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is the leading cause of cancer death in women. At present, chemotherapy is the main method to treat breast cancer in addition to surgery and radiotherapy, but the process of chemotherapy is often accompanied by the development of drug resistance, which leads to a reduction in drug efficacy. Furthermore, mounting evidence indicates that drug resistance is caused by dysregulated cellular metabolism, and metabolic reprogramming, including enhanced glucose metabolism, fatty acid synthesis and glutamine metabolic rates, is one of the hallmarks of cancer. Changes in metabolism have been considered one of the most important causes of resistance to treatment, and knowledge of the mechanisms involved will help in identifying potential treatment deficiencies. To improve women's survival outcomes, it is vital to elucidate the relationship between metabolic reprogramming and drug resistance in breast cancer. This review analyzes and investigates the reprogramming of metabolism and resistance to breast cancer therapy, and the results offer promise for novel targeted and cell-based therapies.
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Affiliation(s)
- Linlin Lv
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, China
| | - Shilei Yang
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yanna Zhu
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaohan Zhai
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shuai Li
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xufeng Tao
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Deshi Dong
- Department of Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China
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21
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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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Nicolas GA, Sudarsa IW, Adiputra PAT, Wihandani DM, Supadmanaba IGP. Relationship between Monocarboxylate Transporter-4 Expression and Breast Cancer Clinicopathology and Subtype in Sanglah General Hospital, Denpasar, Indonesia. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.6934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Based on the global cancer observatory (GLOBOCAN) data, in 2018, there were 18.1 million new breast cancer cases. Breast cancer is the second-most common malignancy after lung cancer, which contributed to 11.6% of all new cancer cases in 2018. Breast cancer is the second-leading cause of death in women in developing countries. The activity of Warburg and reverse Warburg effects on breast cancer is reflected by the expression patterns of two molecules, namely caveolin-1 and monocarboxylate transporter-4 (MCT-4). MCT-4 is a transmembrane transport protein that functions in the transport of lactate from the cytoplasm to the intercellular fluid.
METHODS: This is a cross-sectional analytical study to determine the relationship between MCT-4 expression and breast cancer clinicopathology and subtypes. The study was conducted between April and May of 2020 with 62 breast cancer patients as samples in Sanglah General Hospital, Denpasar. Analysis was done with SPSS 25.
RESULTS: A logistic regression analysis was performed to analyze the relationship between the dependent variable (MCT-4) and covariates (stage, grade, and subtype). Of the three variables that were significantly associated with MCT-4 expression, only clinical stage and subtype (luminal and non-luminal) remained independently associated with MCT-4 expression. Analysis on the clinical stage and subtype variables showed an adjusted OR of 4.727 (p = 0.047; 95% CI: 1.109–21.922) and 17.850 (p = 0.009; 95% CI: 2.069–154.003), respectively. This suggests that MCT-4 has a significant association with subtype and clinical stage which increases the risk of progression of the cancer stage as well as the risk of developing a more malignant (non-luminal) subtype.
CONCLUSION: High MCT-4 expression was significantly associated with malignant subtypes, high histological-grade cancer, and an advanced breast cancer.
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Deng M, Xiong C, He ZK, Bin Q, Song JZ, Li W, Qin J. MCTS1 as a Novel Prognostic Biomarker and Its Correlation With Immune Infiltrates in Breast Cancer. Front Genet 2022; 13:825901. [PMID: 35295953 PMCID: PMC8918534 DOI: 10.3389/fgene.2022.825901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/04/2022] [Indexed: 01/22/2023] Open
Abstract
Multiple copies in T‐cell lymphoma‐1 (MCTS1) plays an important role in various cancers; however, its effects on patient prognosis and immune infiltration in breast cancer remain unclear. In this study, the expression profiles and clinical information of patients with breast cancer were obtained from the Cancer Genome Atlas (TCGA) database. Using the Wilcoxon rank-sum test, the MCTS1 expression levels were compared between breast cancer and normal breast tissues. Functional enrichment analyses were performed to explore the potential signaling pathways and biological functions that are involved. Immune cell infiltration was assessed using single-sample gene set enrichment analysis. The UALCAN and MethSurv databases were used to analyze the methylation status of the MCTS1. The Kaplan-Meier method and Cox regression analysis were used to identify the prognostic value of MCTS1. A nomogram was constructed to predict the overall survival (OS) rates at one-, three-, and five-years post-cancer diagnosis. MCTS1 was overexpressed in breast cancer and significantly associated with the M pathological stage, histological type, PAM50, and increased age. MCTS1 overexpression contributes to a significant decline in OS and disease-specific survival. Multivariate Cox analysis identified MCTS1 as an independent negative prognostic marker of OS. The OS nomogram was generated with a concordance index of 0.715. Similarly, the hypomethylation status of MCTS1 is also associated with poor prognosis. Functional enrichment analysis indicated that the enriched pathways included the reactive oxygen species signaling pathway, MYC targets, interferon alpha response, immune response regulating signaling pathway, and leukocyte migration. Moreover, the overexpression of MCTS1 was negatively correlated with the levels of immune cell infiltration of natural killer cells, CD8+ T cells, effector memory T cells, and plasmacytoid dendritic cells. Therefore, MCTS1 maybe a novel prognostic biomarker.
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Affiliation(s)
- Mei Deng
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
- *Correspondence: Mei Deng,
| | - Chao Xiong
- Department of Information, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Zhuo-Kai He
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Qiong Bin
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jing-Zhi Song
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Wei Li
- Department of Radiation Oncology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jie Qin
- Department of Nuclear Medicine, Affiliated Hospital of Guilin Medical University, Guilin, China
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24
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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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Skaripa-Koukelli I, Hauton D, Walsby-Tickle J, Thomas E, Owen J, Lakshminarayanan A, Able S, McCullagh J, Carlisle RC, Vallis KA. 3-Bromopyruvate-mediated MCT1-dependent metabolic perturbation sensitizes triple negative breast cancer cells to ionizing radiation. Cancer Metab 2021; 9:37. [PMID: 34649623 PMCID: PMC8515664 DOI: 10.1186/s40170-021-00273-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 09/18/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Triple negative breast cancer (TNBC) poses a serious clinical challenge as it is an aggressive form of the disease that lacks estrogen receptor, progesterone receptor, and ERBB2 (formerly HER2) gene amplification, which limits the treatment options. The Warburg phenotype of upregulated glycolysis in the presence of oxygen has been shown to be prevalent in TNBC. Elevated glycolysis satisfies the energy requirements of cancer cells, contributes to resistance to treatment by maintaining redox homeostasis and generating nucleotide precursors required for cell proliferation and DNA repair. Expression of the monocarboxylate transporter 1 (MCT1), which is responsible for the bidirectional transport of lactate, correlates with an aggressive phenotype and poor outcome in several cancer types, including breast cancer. In this study, 3-bromopyruvate (3BP), a lactate/pyruvate analog, was used to selectively target TNBC cells that express MCT1. METHODS The cytotoxicity of 3BP was tested in MTT assays using human TNBC cell lines: BT20 (MCT1+/MCT4-), MDA-MB-23 (MCT1-/MCT4+), and BT20 in which MCT1 was knocked down (siMCT1-BT20). The metabolite profile of 3BP-treated and 3BP-untreated cells was investigated using LC-MS/MS. The extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of BT20 and MDA-MB-231 cells treated with 3BP were measured using a Seahorse XF96 extracellular flux analyzer. The impact of ionizing radiation on cell survival, alone or in combination with 3BP pre-treatment, was evaluated using clonogenic assays. RESULTS Metabolomic analyses showed that 3BP causes inhibition of glycolysis, disturbance of redox homeostasis, decreased nucleotide synthesis, and was accompanied by a reduction in medium acidification. In addition, 3BP potentiated the cytotoxic effect of ionizing radiation, a treatment that is frequently used in the management of TNBC. CONCLUSIONS Overall, MCT1-mediated metabolic perturbation in combination with radiotherapy is shown to be a promising strategy for the treatment of glycolytic tumors such as TNBC, overcoming the selectivity challenges of targeting glycolysis with glucose analogs.
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Affiliation(s)
- Irini Skaripa-Koukelli
- Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
- Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - David Hauton
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK
| | - John Walsby-Tickle
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK
| | - Eloïse Thomas
- Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - Joshua Owen
- Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Abirami Lakshminarayanan
- Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK
| | - Sarah Able
- Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK
| | - James McCullagh
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, OX1 3TA, UK
| | - Robert C Carlisle
- Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK
| | - Katherine A Vallis
- Department of Oncology, Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK.
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26
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Wang X, Liu H, Ni Y, Shen P, Han X. Lactate shuttle: from substance exchange to regulatory mechanism. Hum Cell 2021; 35:1-14. [PMID: 34606041 DOI: 10.1007/s13577-021-00622-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/24/2021] [Indexed: 12/13/2022]
Abstract
Lactate, as the product of glycolytic metabolism and the substrate of energy metabolism, is an intermediate link between cancer cell and tumor microenvironment metabolism. The exchange of lactate between the two cells via mono-carboxylate transporters (MCTs) is known as the lactate shuttle in cancer. Lactate shuttle is the core of cancer cell metabolic reprogramming between two cells such as aerobic cancer cells and hypoxic cancer cells, tumor cells and stromal cells, cancer cells and vascular endothelial cells. Cancer cells absorb lactate by mono-carboxylate transporter 1 (MCT1) and convert lactate to pyruvate via intracellular lactate dehydrogenase B (LDH-B) to maintain their growth and metabolism. Since lactate shuttle may play a critical role in energy metabolism of cancer cells, components related to lactate shuttle may be a crucial target for tumor antimetabolic therapy. In this review, we describe the lactate shuttle in terms of both substance exchange and regulatory mechanisms in cancer. Meanwhile, we summarize the difference of key proteins of lactate shuttle in common types of cancer.
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Affiliation(s)
- Xingchen Wang
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - He Liu
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Yingqian Ni
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Peibo Shen
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China
| | - Xiuzhen Han
- Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China. .,Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan, 250012, China. .,Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan, 250117, Shandong, China.
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27
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Shin E, Koo JS. Glucose Metabolism and Glucose Transporters in Breast Cancer. Front Cell Dev Biol 2021; 9:728759. [PMID: 34552932 PMCID: PMC8450384 DOI: 10.3389/fcell.2021.728759] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/10/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.
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Affiliation(s)
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, Seoul, South Korea
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28
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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression. Rev Physiol Biochem Pharmacol 2021; 182:39-84. [PMID: 34291319 DOI: 10.1007/112_2021_63] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Solid tumors, including breast carcinomas, are heterogeneous but typically characterized by elevated cellular turnover and metabolism, diffusion limitations based on the complex tumor architecture, and abnormal intra- and extracellular ion compositions particularly as regards acid-base equivalents. Carcinogenesis-related alterations in expression and function of ion channels and transporters, cellular energy levels, and organellar H+ sequestration further modify the acid-base composition within tumors and influence cancer cell functions, including cell proliferation, migration, and survival. Cancer cells defend their cytosolic pH and HCO3- concentrations better than normal cells when challenged with the marked deviations in extracellular H+, HCO3-, and lactate concentrations typical of the tumor microenvironment. Ionic gradients determine the driving forces for ion transporters and channels and influence the membrane potential. Cancer and stromal cells also sense abnormal ion concentrations via intra- and extracellular receptors that modify cancer progression and prognosis. With emphasis on breast cancer, the current review first addresses the altered ion composition and the changes in expression and functional activity of ion channels and transporters in solid cancer tissue. It then discusses how ion channels, transporters, and cellular sensors under influence of the acidic tumor microenvironment shape cancer development and progression and affect the potential of cancer therapies.
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29
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Virtanen S, Schulte R, Stingl J, Caldas C, Shehata M. High-throughput surface marker screen on primary human breast tissues reveals further cellular heterogeneity. Breast Cancer Res 2021; 23:66. [PMID: 34120626 PMCID: PMC8201685 DOI: 10.1186/s13058-021-01444-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 05/31/2021] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Normal human breast tissues are a heterogeneous mix of epithelial and stromal subtypes in different cell states. Delineating the spectrum of cellular heterogeneity will provide new insights into normal cellular properties within the breast tissue that might become dysregulated in the initial stages of cancer. Investigation of surface marker expression provides a valuable approach to resolve complex cell populations. However, the majority of cell surface maker expression of primary breast cells have not been investigated. METHODS To determine the differences in expression of a range of uninvestigated cell surface markers between the normal breast cell subpopulations, primary human breast cells were analysed using high-throughput flow cytometry for the expression of 242 cell surface proteins in conjunction with EpCAM/CD49f staining. RESULTS We identified 35 surface marker proteins expressed on normal breast epithelial and/or stromal subpopulations that were previously unreported. We also show multiple markers were equally expressed in all cell populations (e.g. CD9, CD59, CD164) while other surface markers were confirmed to be enriched in different cell lineages: CD24, CD227 and CD340 in the luminal compartment, CD10 and CD90 in the basal population, and CD34 and CD140b on stromal cells. CONCLUSIONS Our dataset of CD marker expression in the normal breast provides better definition for breast cellular heterogeneity.
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Affiliation(s)
- Siru Virtanen
- CRUK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK
| | - Reiner Schulte
- Cambridge Institute for Medical Research, Cambridge University, Cambridge, CB2 0XY, UK
| | - John Stingl
- CRUK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK
| | - Carlos Caldas
- CRUK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK
- Cambridge Breast Unit, Addenbrookes Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Mona Shehata
- CRUK Cambridge Institute, University of Cambridge, Cambridge, CB2 0RE, UK.
- Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge, CB2 0XZ, UK.
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Ghergurovich JM, Lang JD, Levin MK, Briones N, Facista SJ, Mueller C, Cowan AJ, McBride MJ, Rodriguez ESR, Killian A, Dao T, Lamont J, Barron A, Su X, Hendricks WP, Espina V, Von Hoff DD, O’Shaughnessy J, Rabinowitz JD. Local production of lactate, ribose phosphate, and amino acids within human triple-negative breast cancer. MED 2021; 2:736-754. [PMID: 34223403 PMCID: PMC8248508 DOI: 10.1016/j.medj.2021.03.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear. Similarly, the extent to which tumors make biomass precursors from glucose, versus take them up from the circulation, is incompletely defined. METHODS We explore human triple negative breast cancer (TNBC) metabolism by isotope tracing with [1,2-13C]glucose, a tracer that differentiates glycolytic versus oxPPP catabolism and reveals glucose-driven anabolism. Patients enrolled in clinical trial NCT03457779 and received IV infusion of [1,2-13C]glucose during core biopsy of their primary TNBC. Tumor samples were analyzed for metabolite labeling by liquid chromatography-mass spectrometry (LC-MS). Genomic and proteomic analyses were performed and related to observed metabolic fluxes. FINDINGS TNBC ferments glucose to lactate, with glycolysis dominant over the oxPPP. Most ribose phosphate is nevertheless produced by oxPPP. Glucose also feeds amino acid synthesis, including of serine, glycine, aspartate, glutamate, proline and glutamine (but not asparagine). Downstream in glycolysis, tumor pyruvate and lactate labeling exceeds that found in serum, indicating that lactate exchange via monocarboxylic transporters is less prevalent in human TNBC compared with most normal tissues or non-small cell lung cancer. CONCLUSIONS Glucose directly feeds ribose phosphate, amino acid synthesis, lactate, and the TCA cycle locally within human breast tumors.
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Affiliation(s)
- Jonathan M. Ghergurovich
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Jessica D. Lang
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Maren K. Levin
- Baylor Scott & White Research Institute, Dallas, TX 75204, USA
| | - Natalia Briones
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Salvatore J. Facista
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Claudius Mueller
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Alexis J. Cowan
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Matthew J. McBride
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
| | | | - Aaron Killian
- Baylor Scott & White Research Institute, Dallas, TX 75204, USA
| | - Tuoc Dao
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Jeffrey Lamont
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Alison Barron
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Xiaoyang Su
- Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901 USA
| | - William P.D. Hendricks
- Integrated Cancer Genomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Virginia Espina
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA
| | - Daniel D. Von Hoff
- Molecular Medicine Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
| | - Joyce O’Shaughnessy
- Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX 75246, USA
| | - Joshua D. Rabinowitz
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA
- Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
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31
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The tissue expression of MCT3, MCT8, and MCT9 genes in women with breast cancer. Genes Genomics 2021; 43:1065-1077. [PMID: 34097251 DOI: 10.1007/s13258-021-01116-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/27/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Breast cancer (BC) is a common malignancy with a high mortality rate. Malignant cell transformation is associated with metabolic changes. One group of proteins that are affected is the monocarboxylate transporters (MCTs-SLC16A). The MCTs comprise 14 members, and they play an important role in the growth, proliferation, and metabolism of cancer cells by transporting monocarboxylates such as lactate, pyruvate and thyroid hormones. OBJECTIVE We aimed to evaluate the expression of MCT3 (SLC16A8), MCT8 (SLC16A2) and MCT9 (SLC16A9) genes in breast cancer samples, comparing to normal adjacent tissues. METHODS Forty paired breast cancer tumor samples, the adjacent non-tumor and five healthy tissues were collected. Three cancer cell lines (MCF-7, MDA-MB-231, and SKBR3) were also analyzed. The expression of SLC16A8, SLC16A2 and SLC16A9 were assessed using quantitative real-time PCR. The relationship between gene expression with the pathological features of the tumors, and the hormone receptors status of the patient's tumors were also analyzed. RESULTS There was a significantly lower expression of the MCT3 gene in tumor samples compared to adjacent normal tissue and healthy samples (p value < 0.05). There was a significant difference in the expression of all three candidate genes between the BC tissues and normal tissues, and for the, tissues with different hormone receptor status and the molecular subtypes. Altered MCT8 and MCT9 gene expression was associated with a reduced survival CONCLUSION: MCT3 expression is significantly downregulated in breast cancer tissue. MCT3 may represent a novel therapeutic target in breast cancer patients, or in some hormone receptor subgroups.
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32
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Wu Q, Zhang C, He J, Wang C, Hu X, Li N, Zou H, Qin J, Yuan M, Wang Y. Downregulation of caveolin-1 promotes murine breast cancer cell line progression by highly glycosylated CD147. Anticancer Drugs 2021; 32:626-634. [PMID: 33587355 DOI: 10.1097/cad.0000000000001036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Caveolin-1 (CAV-1) can extensively regulate lipid transportation, cell growth and cell death. In the present study, we revealed a novel function of CAV-1 in inhibiting glycosylation of other molecules in murine breast cancer cell line. After the silencing of CAV-1, we found that the mRNA and protein expressions of cluster of differentiation 147 (CD147) and its related molecules (MCT4, matrix metalloproteinase MMP2 and MMP9) increased in the breast cancer cells. Meanwhile, the migration and invasion of the breast cancer cells were significantly enhanced assessed by cell wound healing experiment and transwell assays. Further, the gelatin zymography and lactate assay in the cells also showed the strengthened enzyme activity of MMP9 and the increased extracellular lactate concentration, respectively, after the silencing of CAV-1. Notably, the glycosylation level of CD147 overtly increased after the inhibition of CAV-1 detected by Western Blot analysis, whereas upregulation of CAV-1 did the opposite. Therefore, the findings suggest that the downregulation of CAV-1 can promote breast cancer cell progression probably by highly glycosylated CD147.
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Affiliation(s)
- Qingzhen Wu
- Department of Immunology, School of Medicine, Nankai University
| | - Chao Zhang
- Department of Immunology, School of Medicine, Nankai University
| | - Juan He
- Department of Immunology, School of Medicine, Nankai University
| | - Che Wang
- Department of Immunology, School of Medicine, Nankai University
| | - Xiao Hu
- Department of Immunology, School of Medicine, Nankai University
| | - Ning Li
- Institute of Disaster Medicine, Tianjin University, Tianjin, China
| | - Huiru Zou
- Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, The Affiliated Stomatological Hospital of Nankai University
| | - Junfang Qin
- Department of Immunology, School of Medicine, Nankai University
| | - Mengci Yuan
- Department of Immunology, School of Medicine, Nankai University
| | - Yue Wang
- Department of Immunology, School of Medicine, Nankai University
- Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, The Affiliated Stomatological Hospital of Nankai University
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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: 22] [Impact Index Per Article: 5.5] [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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Fairweather SJ, Shah N, Brӧer S. Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 21:13-127. [PMID: 33052588 DOI: 10.1007/5584_2020_584] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture.
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Affiliation(s)
- Stephen J Fairweather
- Research School of Biology, Australian National University, Canberra, ACT, Australia. .,Resarch School of Chemistry, Australian National University, Canberra, ACT, Australia.
| | - Nishank Shah
- Research School of Biology, Australian National University, Canberra, ACT, Australia
| | - Stefan Brӧer
- Research School of Biology, Australian National University, Canberra, ACT, Australia.
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Leu M, Kitz J, Pilavakis Y, Hakroush S, Wolff HA, Canis M, Rieken S, Schirmer MA. Monocarboxylate transporter-1 (MCT1) protein expression in head and neck cancer affects clinical outcome. Sci Rep 2021; 11:4578. [PMID: 33633176 PMCID: PMC7907348 DOI: 10.1038/s41598-021-84019-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 02/04/2021] [Indexed: 01/31/2023] Open
Abstract
Treatment of locally advanced, unresectable head and neck squamous cell carcinoma (HNSCC) often yields only modest results with radiochemotherapy (RCT) as standard of care. Prognostic features related to outcome upon RCT might be highly valuable to improve treatment. Monocarboxylate transporters-1 and -4 (MCT1/MCT4) were evaluated as potential biomarkers. A cohort of HNSCC patients without signs for distant metastases was assessed eliciting 82 individuals eligible whereof 90% were diagnosed with locally advanced stage IV. Tumor specimens were stained for MCT1 and MCT4 in the cell membrane by immunohistochemistry. Obtained data were evaluated with respect to overall (OS) and progression-free survival (PFS). Protein expression of MCT1 and MCT4 in cell membrane was detected in 16% and 85% of the tumors, respectively. Expression of both transporters was not statistically different according to the human papilloma virus (HPV) status. Positive staining for MCT1 (n = 13, negative in n = 69) strongly worsened PFS with a hazard ratio (HR) of 3.1 (95%-confidence interval 1.6-5.7, p < 0.001). OS was likewise affected with a HR of 3.8 (2.0-7.3, p < 0.001). Multivariable Cox regression confirmed these findings. We propose MCT1 as a promising biomarker in HNSCC treated by primary RCT.
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Affiliation(s)
- Martin Leu
- grid.411984.10000 0001 0482 5331Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - J. Kitz
- grid.411984.10000 0001 0482 5331Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - Y. Pilavakis
- grid.411984.10000 0001 0482 5331Clinic of Otorhinolaryngology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - S. Hakroush
- grid.411984.10000 0001 0482 5331Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - H. A. Wolff
- Department of Radiology, Nuclear Medicine and Radiotherapy, Radiology Munich, Maximiliansplatz 2, 80333 Munich, Germany ,grid.7727.50000 0001 2190 5763Department of Radiation Oncology, Medical Center, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany
| | - M. Canis
- grid.5252.00000 0004 1936 973XDepartment of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377 Munich, Germany
| | - S. Rieken
- grid.411984.10000 0001 0482 5331Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
| | - M. A. Schirmer
- grid.411984.10000 0001 0482 5331Clinic of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
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Benyahia Z, Blackman MCNM, Hamelin L, Zampieri LX, Capeloa T, Bedin ML, Vazeille T, Schakman O, Sonveaux P. In Vitro and In Vivo Characterization of MCT1 Inhibitor AZD3965 Confirms Preclinical Safety Compatible with Breast Cancer Treatment. Cancers (Basel) 2021; 13:cancers13030569. [PMID: 33540599 PMCID: PMC7867268 DOI: 10.3390/cancers13030569] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/24/2021] [Accepted: 01/30/2021] [Indexed: 12/04/2022] Open
Abstract
Simple Summary The vast majority of tumors originate in tissues that use different substrates and oxygen to produce energy. However, tumors are disorganized structurally and functionally, which creates areas where oxygen and nutrients are poorly available. To survive and proliferate, cancer cells adapt by switching their metabolism to lactic fermentation. Their fate is further optimized by intercellular cooperation, but this creates a weakness that can be exploited therapeutically. Indeed, AZD3965 is a new drug currently tested in clinical trials that inhibits a cooperation based on lactate swapping for glucose between fermenting and respiring cells. It inhibits lactate transporter monocarboxylate transporter 1. Here, using malignant and nonmalignant cells representative of the breast tissue and several behavioral tests in mice, we establish that AZD3965 is safe for therapeutic use against cancer. The only side effect that we detected was a short-term memory retention defect that transiently perturbed the orientation of mice in space. Abstract To survive and proliferate in solid tumors, cancer cells adapt and evolve rapidly in microenvironments where oxygen and substrate bioavailability fluctuates over time and space. This creates metabolic heterogeneity. Cancer cells can further cooperate metabolically, for example by swapping glycolytic end-product lactate for blood-borne glucose. This type of cooperation can be targeted therapeutically, since transmembrane lactate exchanges are facilitated by lactate-proton symporters of the monocarboxylate (MCT) family. Among new drugs, AZD3965 is a first-in-class selective MCT1 inhibitor currently tested in Phase I/II clinical trials for patients with different types of cancers. Because MCT1 can function bidirectionally, we tested here whether and how malignant and nonmalignant cells adapt their metabolism and MCT repertoire when AZD3965 inhibits either lactate import or export. Using breast-associated malignant and nonmalignant cell lines as models, we report that AZD3965 is not directly cytotoxic. In the presence of glucose and glutamine, oxidative cells can survive when lactate uptake is blocked, and proliferating cells compensate MCT1 inhibition by overexpressing MCT4, a specialized facilitator of lactate export. Phenotypic characterization of mice focusing on metabolism, muscle and brain physiology found partial and transient memory retention defect as sole consequence of MCT1 inhibition by AZD3965. We therefore conclude that AZD3965 is compatible with anticancer therapy.
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Affiliation(s)
- Zohra Benyahia
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Marine C. N. M. Blackman
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Loïc Hamelin
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Luca X. Zampieri
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Tania Capeloa
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Marie L. Bedin
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Thibaut Vazeille
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
| | - Olivier Schakman
- Pole of Cell Physiology, Institut des Neurosciences (IoNS), Université Catholique de Louvain (UCLouvain), Avenue E. Mounier 53 box B1.53.17, 1200 Brussels, Belgium;
| | - Pierre Sonveaux
- Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium; (Z.B.); (M.C.N.M.B.); (L.H.); (L.X.Z.); (T.C.); (M.L.B.); (T.V.)
- Correspondence:
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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: 23] [Impact Index Per Article: 5.8] [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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Naik A, Decock J. Lactate Metabolism and Immune Modulation in Breast Cancer: A Focused Review on Triple Negative Breast Tumors. Front Oncol 2020; 10:598626. [PMID: 33324565 PMCID: PMC7725706 DOI: 10.3389/fonc.2020.598626] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/30/2020] [Indexed: 12/19/2022] Open
Abstract
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with poor prognosis, early recurrence, and the lack of durable chemotherapy responses and specific targeted treatments. The recent FDA approval for immune checkpoint inhibition in combination with nab-paclitaxel for the treatment of metastatic TNBC created opportunity to advocate for immunotherapy in TNBC patients. However, improving the current low response rates is vital. Most cancers, including TNBC tumors, display metabolic plasticity and undergo reprogramming into highly glycolytic tumors through the Warburg effect. Consequently, accumulation of the metabolic byproduct lactate and extracellular acidification is often observed in several solid tumors, thereby exacerbating tumor cell proliferation, metastasis, and angiogenesis. In this review, we focus on the role of lactate acidosis in the microenvironment of glycolytic breast tumors as a major driver for immune evasion with a special emphasis on TNBCs. In particular, we will discuss the role of lactate regulators such as glucose transporters, lactate dehydrogenases, and lactate transporters in modulating immune functionality and checkpoint expression in numerous immune cell types. This review aims to spark discussion on interventions targeting lactate acidosis in combination with immunotherapy to provide an effective means of improving response to immune checkpoint inhibitors in TNBC, in addition to highlighting challenges that may arise from TNBC tumor heterogeneity.
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Affiliation(s)
- Adviti Naik
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Julie Decock
- Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
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Harguindey S, Alfarouk K, Polo Orozco J, Fais S, Devesa J. Towards an Integral Therapeutic Protocol for Breast Cancer Based upon the New H +-Centered Anticancer Paradigm of the Late Post-Warburg Era. Int J Mol Sci 2020; 21:E7475. [PMID: 33050492 PMCID: PMC7589677 DOI: 10.3390/ijms21207475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/05/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
A brand new approach to the understanding of breast cancer (BC) is urgently needed. In this contribution, the etiology, pathogenesis, and treatment of this disease is approached from the new pH-centric anticancer paradigm. Only this unitarian perspective, based upon the hydrogen ion (H+) dynamics of cancer, allows for the understanding and integration of the many dualisms, confusions, and paradoxes of the disease. The new H+-related, wide-ranging model can embrace, from a unique perspective, the many aspects of the disease and, at the same time, therapeutically interfere with most, if not all, of the hallmarks of cancer known to date. The pH-related armamentarium available for the treatment of BC reviewed here may be beneficial for all types and stages of the disease. In this vein, we have attempted a megasynthesis of traditional and new knowledge in the different areas of breast cancer research and treatment based upon the wide-ranging approach afforded by the hydrogen ion dynamics of cancer. The concerted utilization of the pH-related drugs that are available nowadays for the treatment of breast cancer is advanced.
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Affiliation(s)
- Salvador Harguindey
- Department of Oncology, Institute of Clinical Biology and Metabolism, 01004 Vitoria, Spain;
| | - Khalid Alfarouk
- Department of Pharmacology, Al-Ghad International Colleges for Applied Medical Sciences, Al-Madinah Al-Munawarah 42316, Saudi Arabia and Alfarouk Biomedical Research LLC, Tampa, FL 33617, USA;
| | - Julián Polo Orozco
- Department of Oncology, Institute of Clinical Biology and Metabolism, 01004 Vitoria, Spain;
| | - Stefano Fais
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità (National Institute of Health), 00161 Rome, Italy;
| | - Jesús Devesa
- Scientific Direction, Foltra Medical Centre, 15886 Teo, Spain;
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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: 83] [Impact Index Per Article: 16.6] [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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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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43
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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: 30] [Impact Index Per Article: 6.0] [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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Targeted cancer therapy using alpha-cyano-4-hydroxycinnamic acid as a novel vector molecule: A proof-of-concept study. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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45
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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: 106] [Impact Index Per Article: 21.2] [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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Orellana-Tavra C, Köppen M, Li A, Stock N, Fairen-Jimenez D. Biocompatible, Crystalline, and Amorphous Bismuth-Based Metal-Organic Frameworks for Drug Delivery. ACS APPLIED MATERIALS & INTERFACES 2020; 12:5633-5641. [PMID: 31940165 DOI: 10.1021/acsami.9b21692] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The synthetic flexibility of metal-organic frameworks (MOFs) with high loading capacities and biocompatibility makes them ideal candidates as drug delivery systems (DDSs). Here, we report the use of CAU-7, a biocompatible bismuth-based MOF, for the delivery of two cancer drugs, sodium dichloroacetate (DCA) and α-cyano-4-hydroxycinnamic acid (α-CHC). We achieved loadings of 33 and 9 wt % for DCA and α-CHC, respectively. Interestingly, CAU-7 showed a gradual release of the drugs, achieving a release time of up to 17 days for DCA and 31 days for α-CHC. We then performed mechanical and thermal amorphization processes to attempt to delay the delivery of guest molecules even more. With the thermal treatment, we were able to achieve an outstanding 32% slower release of α-CHC from the thermally treated CAU-7. Using in vitro studies and endocytosis inhibitors, confocal microscopy, and fluorescence-activated cell sorting, we also demonstrated that CAU-7 was successfully internalized by cancer cells, partially avoiding lysosome degradation. Finally, we showed that CAU-7 loaded either with DCA or α-CHC had a higher therapeutic efficiency compared with the free drug approach, making CAU-7 a great option for biomedical application.
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Affiliation(s)
- Claudia Orellana-Tavra
- Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering & Biotechnology , University of Cambridge , Philippa Fawcett Drive , Cambridge CB3 0AS , U.K
| | - Milan Köppen
- Institut für Anorganische Chemie , Max-Eyth-Straße 2 , Kiel D-24118 , Germany
| | - Aurelia Li
- Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering & Biotechnology , University of Cambridge , Philippa Fawcett Drive , Cambridge CB3 0AS , U.K
| | - Norbert Stock
- Institut für Anorganische Chemie , Max-Eyth-Straße 2 , Kiel D-24118 , Germany
| | - David Fairen-Jimenez
- Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering & Biotechnology , University of Cambridge , Philippa Fawcett Drive , Cambridge CB3 0AS , U.K
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Becker HM. Carbonic anhydrase IX and acid transport in cancer. Br J Cancer 2020; 122:157-167. [PMID: 31819195 PMCID: PMC7051959 DOI: 10.1038/s41416-019-0642-z] [Citation(s) in RCA: 136] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 08/29/2019] [Accepted: 10/22/2019] [Indexed: 02/07/2023] Open
Abstract
Alterations in tumour metabolism and acid/base regulation result in the formation of a hostile environment, which fosters tumour growth and metastasis. Acid/base homoeostasis in cancer cells is governed by the concerted interplay between carbonic anhydrases (CAs) and various transport proteins, which either mediate proton extrusion or the shuttling of acid/base equivalents, such as bicarbonate and lactate, across the cell membrane. Accumulating evidence suggests that some of these transporters interact both directly and functionally with CAIX to form a protein complex coined the 'transport metabolon'. Transport metabolons formed between bicarbonate transporters and CAIX require CA catalytic activity and have a function in cancer cell migration and invasion. Another type of transport metabolon is formed by CAIX and monocarboxylate transporters. In this complex, CAIX functions as a proton antenna for the transporter, which drives the export of lactate and protons from the cell. Since CAIX is almost exclusively expressed in cancer cells, these transport metabolons might serve as promising targets to interfere with tumour pH regulation and energy metabolism. This review provides an overview of the current state of research on the function of CAIX in tumour acid/base transport and discusses how CAIX transport metabolons could be exploited in modern cancer therapy.
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Affiliation(s)
- Holger M Becker
- Institute of Physiological Chemistry, University of Veterinary Medicine Hannover, D-30559, Hannover, Germany.
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Sun Y, Sun J, He Z, Wang G, Wang Y, Zhao D, Wang Z, Luo C, Tian C, Jiang Q. Monocarboxylate Transporter 1 in Brain Diseases and Cancers. Curr Drug Metab 2019; 20:855-866. [DOI: 10.2174/1389200220666191021103018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/21/2019] [Accepted: 10/04/2019] [Indexed: 12/14/2022]
Abstract
Background:
Monocarboxylate Transporter 1 (MCT1), an important membrane transport protein, mediates
the translocation of monocarboxylates together with protons across biological membranes. Due to its pathological
significance, MCT1 plays an important role in the progression of some diseases, such as brain diseases and cancers.
Methods:
We summarize the general description of MCT1 and provide a comprehensive understanding of the role of
MCT1 in brain diseases and cancers. Furthermore, this review discusses the opportunities and challenges of MCT1-
targeting drug-delivery systems in the treatment of brain diseases and cancers.
Results:
In the brain, loss of MCT1 function is associated with pathologies of degeneration and injury of the nervous
system. In tumors, MCT1 regulates the activity of signaling pathways and controls the exchange of monocarboxylates
in aerobic glycolysis to affect tumor metabolism, proliferation and invasion. Meanwhile, MCT1 also acts as a
good biomarker for the prediction and diagnosis of cancer progressions.
Conclusion:
MCT1 is an attractive transporter in brain diseases and cancers. Moreover, the development of MCT1-
based small molecule drugs and MCT1 inhibitors in the clinic is promising. This review systematically summarizes
the basic characteristics of MCT1 and its role in brain diseases and cancers, laying the foundation for further research
on MCT1.
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Affiliation(s)
- Yixin Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jin Sun
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhonggui He
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Gang Wang
- School of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Yang Wang
- School of Pharmacy, Guangxi University of Chinese Medicine, Nanning 530200, China
| | - Dongyang Zhao
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Zhenjie Wang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Cong Luo
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Chutong Tian
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Qikun Jiang
- Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
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Pedroza-Torres A, Romero-Córdoba SL, Justo-Garrido M, Salido-Guadarrama I, Rodríguez-Bautista R, Montaño S, Muñiz-Mendoza R, Arriaga-Canon C, Fragoso-Ontiveros V, Álvarez-Gómez RM, Hernández G, Herrera LA. MicroRNAs in Tumor Cell Metabolism: Roles and Therapeutic Opportunities. Front Oncol 2019; 9:1404. [PMID: 31921661 PMCID: PMC6917641 DOI: 10.3389/fonc.2019.01404] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 11/27/2019] [Indexed: 12/16/2022] Open
Abstract
Dysregulated metabolism is a common feature of cancer cells and is considered a hallmark of cancer. Altered tumor-metabolism confers an adaptive advantage to cancer cells to fulfill the high energetic requirements for the maintenance of high proliferation rates, similarly, reprogramming metabolism confers the ability to grow at low oxygen concentrations and to use alternative carbon sources. These phenomena result from the dysregulated expression of diverse genes, including those encoding microRNAs (miRNAs) which are involved in several metabolic and tumorigenic pathways through its post-transcriptional-regulatory activity. Further, the identification of key actionable altered miRNA has allowed to propose novel targeted therapies to modulated tumor-metabolism. In this review, we discussed the different roles of miRNAs in cancer cell metabolism and novel miRNA-based strategies designed to target the metabolic machinery in human cancer.
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Affiliation(s)
- Abraham Pedroza-Torres
- Cátedra CONACyT-Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Sandra L Romero-Córdoba
- Departamento de Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - Montserrat Justo-Garrido
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Iván Salido-Guadarrama
- Biología Computacional, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", Mexico City, Mexico
| | - Rubén Rodríguez-Bautista
- Unidad de Oncología Torácica y Laboratorio de Medicina Personalizada, Instituto Nacional de Cancerologia, Mexico City, Mexico
| | - Sarita Montaño
- Laboratorio de Bioinformática, Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Sinaloa (FCQB-UAS), Culiacán, Mexico
| | - Rodolfo Muñiz-Mendoza
- Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Cristian Arriaga-Canon
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | | | | | - Greco Hernández
- Laboratorio de Traducción y Cáncer, Unidad de Investigaciones Biomedicas en Cáncer, Instituto Nacional de Cancerolgía, Mexico City, Mexico
| | - Luis A Herrera
- Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología - Instituto de Investigaciones Biomédicas - Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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50
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Alves WEFM, Bonatelli M, Dufloth R, Kerr LM, Carrara GFA, da Costa RFA, Scapulatempo-Neto C, Tiezzi D, da Costa Vieira RA, Pinheiro C. CAIX is a predictor of pathological complete response and is associated with higher survival in locally advanced breast cancer submitted to neoadjuvant chemotherapy. BMC Cancer 2019; 19:1173. [PMID: 31795962 PMCID: PMC6889185 DOI: 10.1186/s12885-019-6353-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/11/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Locally advanced breast cancer often undergoes neoadjuvant chemotherapy (NAC), which allows in vivo evaluation of the therapeutic response. The determination of the pathological complete response (pCR) is one way to evaluate the response to neoadjuvant chemotherapy. However, the rate of pCR differs significantly between molecular subtypes and the cause is not yet determined. Recently, the metabolic reprogramming of cancer cells and its implications for tumor growth and dissemination has gained increasing prominence and could contribute to a better understanding of NAC. Thus, this study proposed to evaluate the expression of metabolism-related proteins and its association with pCR and survival rates. METHODS The expression of monocarboxylate transporters 1 and 4 (MCT1 and MCT4, respectively), cluster of differentiation 147 (CD147), glucose transporter-1 (GLUT1) and carbonic anhydrase IX (CAIX) was analyzed in 196 locally advanced breast cancer samples prior to NAC. The results were associated with clinical-pathological characteristics, occurrence of pCR, disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS). RESULTS The occurrence of pCR was higher in the group of patients whith tumors expressing GLUT1 and CAIX than in the group without expression (27.8% versus 13.1%, p = 0.030 and 46.2% versus 13.5%, p = 0.007, respectively). Together with regional lymph nodes staging and mitotic staging, CAIX expression was considered an independent predictor of pCR. In addition, CAIX expression was associated with DFS and DSS (p = 0.005 and p = 0.012, respectively). CONCLUSIONS CAIX expression was a predictor of pCR and was associated with higher DFS and DSS in locally advanced breast cancer patients subjected to NAC.
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Affiliation(s)
- Wilson Eduardo Furlan Matos Alves
- Nuclear Medicine and Molecular Imaging Department, Barretos Cancer Hospital - Pio XII Foundation, Rua Antenor Duarte Vilela, N° 1331, Barretos, São Paulo, 14784-400, Brazil. .,Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
| | - Murilo Bonatelli
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Rozany Dufloth
- Pathology Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | - Lígia Maria Kerr
- Pathology Department, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
| | | | - Ricardo Filipe Alves da Costa
- Research and Teaching Institute, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.,Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil
| | | | - Daniel Tiezzi
- Department of Gynecology and Obstetrics - Breast Disease Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribreirão Preto, São Paulo, Brazil
| | | | - Céline Pinheiro
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.,Barretos School of Health Sciences Dr. Paulo Prata - FACISB, Barretos, São Paulo, Brazil
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