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1
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Yang D, Yang C, Huang L, Guan M, Song C. Role of ubiquitination-driven metabolisms in oncogenesis and cancer therapy. Semin Cancer Biol 2025; 110:17-35. [PMID: 39929409 DOI: 10.1016/j.semcancer.2025.02.004] [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: 08/26/2024] [Revised: 01/17/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025]
Abstract
Ubiquitination represents one of the most critical post-translational modifications, comprising a multi-stage enzyme process that plays a pivotal role in a myriad of cellular biological activities. The deregulation of the processes of ubiquitination and deubiquitination is associated with the development of cancers and other diseases. This typescript reviews the impact of ubiquitination on metabolic processes, elucidating the regulatory functions of ubiquitination on pivotal enzymes within metabolic pathways in pathological contexts. It underscores the role of ubiquitination-driven metabolism disorders in the etiology of cancers, and oncogenesis, and highlights the potential therapeutic efficacy of targeting ubiquitination-driven enzymes in cancer metabolism, their combination with immune checkpoint inhibitors, and their clinical applications.
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Affiliation(s)
- Dongqin Yang
- Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai 200040, China; Central Laboratory, Huashan Hospital, Fudan University, 12 Middle Urumuqi Road, Shanghai 200040, China
| | - Can Yang
- Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Linlin Huang
- Central Laboratory, Huashan Hospital, Fudan University, 12 Middle Urumuqi Road, Shanghai 200040, China
| | - Ming Guan
- Department of Laboratory Medicine of Huashan Hospital, Fudan University, Shanghai 200040, China.
| | - Chunhua Song
- Division of Hematology, The Ohio State University Wexner Medical Center, the James Cancer Hospital, Columbus, OH 43210, USA.
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2
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Zhang W, Xia M, Li J, Liu G, Sun Y, Chen X, Zhong J. Warburg effect and lactylation in cancer: mechanisms for chemoresistance. Mol Med 2025; 31:146. [PMID: 40264038 PMCID: PMC12016192 DOI: 10.1186/s10020-025-01205-6] [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: 02/18/2025] [Accepted: 04/09/2025] [Indexed: 04/24/2025] Open
Abstract
In the clinical management of cancers, the emergence of chemoresistance represents a profound and imperative "pain point" that requires immediate attention. Understanding the mechanisms of chemoresistance is essential for developing effective therapeutic strategies. Importantly, existing studies have demonstrated that glucose metabolic reprogramming, commonly referred to as the Warburg effect or aerobic glycolysis, is a major contributor to chemoresistance. Additionally, lactate, a byproduct of aerobic glycolysis, functions as a signaling molecule that supports lysine lactylation modification of proteins, which also plays a critical role in chemoresistance. However, it is insufficient to discuss the role of glycolysis or lactylation in chemoresistance from a single perspective. The intricate relationship between aerobic glycolysis and lactylation plays a crucial role in promoting chemoresistance. Thus, a thorough elucidation of the mechanisms underlying chemoresistance mediated by aerobic glycolysis and lactylation is essential. This review provides a comprehensive overview of these mechanisms and further outlines that glycolysis and lactylation exert synergistic effects, promoting the development of chemoresistance and creating a positive feedback loop that continues to mediate this resistance. The close link between aerobic glycolysis and lactylation suggests that the application of glycolysis-related drugs or inhibitors in cancer therapy may represent a promising anticancer strategy. Furthermore, the targeted application of lactylation, either alone or in combination with other treatments, may offer new therapeutic avenues for overcoming chemoresistance.
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Affiliation(s)
- Wenjie Zhang
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Min Xia
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Jiahui Li
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Gaohua Liu
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Yan Sun
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Xisha Chen
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
| | - Jing Zhong
- Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
- Institute of Cancer Research, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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Shan W, Zhang SL, Assaraf YG, Tam KY. Combined inhibition of hexokinase 2 and pyruvate dehydrogenase surmounts SHP2 inhibitor resistance in non-small cell lung cancer with hybrid metabolic state harboring KRAS Q61H mutation. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167859. [PMID: 40250775 DOI: 10.1016/j.bbadis.2025.167859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 03/02/2025] [Accepted: 04/15/2025] [Indexed: 04/20/2025]
Abstract
KRAS Q61H is an aggressive oncogenic driver mutation rendering cancer cells drug resistant to SHP2 inhibitors (SHP2i). Some metastatic and chemoresistant non-small cell lung cancer (NSCLC) cells, exhibit a hybrid metabolic state in which both glycolysis and oxidative phosphorylation (OXPHOS) coexist. Hence, we evaluated the in vitro and in vivo efficacy of a combination of hexokinase 2 (HK2) and pyruvate dehydrogenase (PDH) inhibitors, benserazide (Benz) and CPI-613, respectively, against NSCLC NCI-H460 cells harboring the driver KRAS Q61H mutation. This combination synergistically disrupted the hybrid metabolic state, inhibited NCI-H460 cell proliferation in vitro, and markedly suppressed tumor growth in NCI-H460 cell xenograft model in mice. The molecular basis underlying this antitumor activity was apparently due to suppression of SHP2/SOS1/RAS/MAPK signaling pathways, leading to enhanced apoptosis. Moreover, this drug combination restored the sensitivity to SHP2i. Consistently, SHP2 overexpression in NCI-H460 cells abrogated the antitumor activity of this drug combination. These findings reveal that the combination of Benz and CPI-613 targets the metabolic vulnerability of KRAS Q61H mutant-bearing NSCLC tumors. These results offer a combination therapeutic strategy for the possible treatment of cancer cells displaying a hybrid metabolic state, thereby surmounting chemoresistance.
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Affiliation(s)
- Wenying Shan
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Shao-Lin Zhang
- School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 401331, PR China
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
| | - Kin Yip Tam
- Faculty of Health Sciences, University of Macau, Taipa, Macau.
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Jin Y, Qi M, Si L, Shi X, Cai M, Fu H, Liu Y, Guo R. IGFBP2 Promotes Proliferation and Glycolysis of Endometrial Cancer by Regulating PKM2/HIF-1α Axis. Cancer Sci 2025; 116:656-672. [PMID: 39761954 PMCID: PMC11875784 DOI: 10.1111/cas.16447] [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: 08/10/2024] [Revised: 12/02/2024] [Accepted: 12/23/2024] [Indexed: 03/05/2025] Open
Abstract
Endometrial cancer (EC) is a worldwide gynecologic malignancies, with a remarking increase of incidence and mortality rates in recent years. Growing evidence indicates that glucose metabolism reprogramming is the most representative metabolic signature of tumor cells and exploring its modulatory function in EC development will promote identifying potential EC therapeutic targets. IGFBP2 is an insulin-like growth factor binding protein which is closely associated with a variety of metabolic diseases. However, its biological role in EC and its effects on glucose metabolism remain unclear. In this study, we demonstrated that IGFBP2 was highly expressed in EC tissues and correlated with poor prognosis. Overexpression of IGFBP2 promoted proliferation and glycolysis in EC cells, whereas IGFBP2 knockdown had the opposite effect. Mechanistically, IGFBP2 directly interacted with PKM2, inducing weakened PKM2 protein degradation, and knockdown IGFBP2 expression prevented the translocation of PKM2 to the nucleus. Additionally, IGFBP2 expression was upregulated under the condition of hypoxia which directly regulated by transcriptional activation of HIF-1α. Finally, the role of the IGFBP2/PKM2/HIF-1α axis in EC tumor growth was confirmed in vivo using mouse xenograft models. Taken together, the current study identifies IGFBP2 as an upstream activator of PKM2-driven proliferation and glycolysis in EC cells, providing a promising therapeutic target for EC.
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Affiliation(s)
- Yuxi Jin
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological TumorZhengzhouHenanChina
| | - Meng Qi
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological TumorZhengzhouHenanChina
| | - Lulu Si
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological TumorZhengzhouHenanChina
| | - Xiaojing Shi
- Laboratory Animal Center, State Key Laboratory of Esophageal Cancer Prevention & TreatmentZhengzhou UniversityZhengzhouHenanChina
| | - Mingbo Cai
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Hanlin Fu
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological TumorZhengzhouHenanChina
| | - Yana Liu
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological TumorZhengzhouHenanChina
| | - Ruixia Guo
- Department of GynecologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- Medical Key Laboratory for Prevention and Treatment of Malignant Gynecological TumorZhengzhouHenanChina
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Huggler KS, Mellado Fritz CA, Flickinger KM, Chang GR, McGuire MF, Cantor JR. Hexokinase detachment from mitochondria drives the Warburg effect to support compartmentalized ATP production. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.07.637120. [PMID: 39975027 PMCID: PMC11839068 DOI: 10.1101/2025.02.07.637120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Hexokinase (HK) catalyzes the synthesis of glucose-6-phosphate, marking the first committed step of glucose metabolism. Most cancer cells express two homologous isoforms (HK1 and HK2) that can each bind to the outer mitochondrial membrane (OMM). CRISPR screens across hundreds of cancer cell lines indicate that both are dispensable for cell growth in traditional culture media. By contrast, HK2 deletion impairs cell growth in Human Plasma-Like Medium (HPLM). Here, we find that HK2 is required to maintain sufficient cytosolic (OMM-detached) HK activity under conditions that enhance HK1 binding to the OMM. Notably, OMM-detached rather than OMM-docked HK promotes "aerobic glycolysis" (Warburg effect), an enigmatic phenotype displayed by most proliferating cells. We show that several proposed theories for this phenotype cannot explain the HK2 dependence and instead find that HK2 deletion severely impairs glycolytic ATP production with little impact on total ATP yield for cells in HPLM. Our results reveal a basis for conditional HK2 essentiality and suggest that demand for compartmentalized ATP synthesis underlies the Warburg effect.
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Komza M, Khatun J, Gelles JD, Trotta AP, Abraham-Enachescu I, Henao J, Elsaadi A, Kotini AG, Clementelli C, Arandela J, Ghaity-Beckley SE, Barua A, Chen Y, Berisa M, Marcellino BK, Papapetrou EP, Poyurovsky MV, Chipuk JE. Metabolic adaptations to acute glucose uptake inhibition converge upon mitochondrial respiration for leukemia cell survival. Cell Commun Signal 2025; 23:47. [PMID: 39863913 PMCID: PMC11762851 DOI: 10.1186/s12964-025-02044-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.
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MESH Headings
- Humans
- Mitochondria/metabolism
- Mitochondria/drug effects
- Glucose/metabolism
- Cell Survival/drug effects
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/drug therapy
- Cell Respiration/drug effects
- Glycolysis/drug effects
- Oxidative Phosphorylation/drug effects
- Cell Line, Tumor
- Adaptation, Physiological
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Affiliation(s)
- Monika Komza
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Present Address: Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 441, New York, NY, 10065, USA
| | - Jesminara Khatun
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Jesse D Gelles
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Andrew P Trotta
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Ioana Abraham-Enachescu
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Juan Henao
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Ahmed Elsaadi
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Andriana G Kotini
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Cara Clementelli
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - JoAnn Arandela
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Sebastian El Ghaity-Beckley
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Agneesh Barua
- Department of Ecology and Evolution, University of Lausanne, Biophore, 1015, Lausanne, CH, Switzerland
| | - Yiyang Chen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Mirela Berisa
- Metabolomics Core, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Bridget K Marcellino
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Eirini P Papapetrou
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Center for Advancement of Blood Cancer Therapies, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Masha V Poyurovsky
- Kadmon Pharmaceuticals, 450 East 29th Street, New York, NY, 10016, USA
- Present address: PMV Pharmaceuticals, Inc., 1 Research Way, Princeton, NJ, 08540, USA
| | - Jerry Edward Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
- The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
- The Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, Box 1130, 1425 Madison Avenue, New York, NY, 10029, USA.
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7
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Hao ZN, Tan XP, Zhang Q, Li J, Xia R, Ma Z. Lactate and Lactylation: Dual Regulators of T-Cell-Mediated Tumor Immunity and Immunotherapy. Biomolecules 2024; 14:1646. [PMID: 39766353 PMCID: PMC11674224 DOI: 10.3390/biom14121646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/14/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025] Open
Abstract
Lactate and its derivative, lactylation, play pivotal roles in modulating immune responses within the tumor microenvironment (TME), particularly in T-cell-mediated cancer immunotherapy. Elevated lactate levels, a hallmark of the Warburg effect, contribute to immune suppression through CD8+ T cell functionality and by promoting regulatory T cell (Treg) activity. Lactylation, a post-translational modification (PTM), alters histone and non-histone proteins, influencing gene expression and further reinforcing immune suppression. In the complex TME, lactate and its derivative, lactylation, are not only associated with immune suppression but can also, under certain conditions, exert immunostimulatory effects that enhance cytotoxic responses. This review describes the dual roles of lactate and lactylation in T-cell-mediated tumor immunity, analyzing how these factors contribute to immune evasion, therapeutic resistance, and immune activation. Furthermore, the article highlights emerging therapeutic strategies aimed at inhibiting lactate production or disrupting lactylation pathways to achieve a balanced regulation of these dual effects. These strategies offer new insights into overcoming tumor-induced immune suppression and hold the potential to improve the efficacy of cancer immunotherapies.
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Affiliation(s)
- Zhi-Nan Hao
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Xiao-Ping Tan
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
- The Third Clinical Medical College of Yangtze University, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou 434023, China
| | - Qing Zhang
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Jie Li
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- Digestive Disease Research Institution of Yangtze University, Yangtze University, Jingzhou 434023, China;
| | - Ruohan Xia
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
| | - Zhaowu Ma
- Department of Gastroenterology, First Affiliated Hospital of Yangtze University, Health Science Center, Yangtze University, Jingzhou 434023, China; (Z.-N.H.); (Q.Z.); (J.L.)
- School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou 434023, China
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8
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Liu J, Zhou F, Tang Y, Li L, Li L. Progress in Lactate Metabolism and Its Regulation via Small Molecule Drugs. Molecules 2024; 29:5656. [PMID: 39683818 DOI: 10.3390/molecules29235656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Lactate, once viewed as a byproduct of glycolysis and a metabolic "waste", is now recognized as an energy-providing substrate and a signaling molecule that modulates cellular functions under pathological conditions. The discovery of histone lactylation in 2019 marked a paradigm shift, with subsequent studies revealing that lactate can undergo lactylation with both histone and non-histone proteins, implicating it in the pathogenesis of various diseases, including cancer, liver fibrosis, sepsis, ischemic stroke, and acute kidney injury. Aberrant lactate metabolism is associated with disease onset, and its levels can predict disease outcomes. Targeting lactate production, transport, and lactylation may offer therapeutic potential for multiple diseases, yet a systematic summary of the small molecules modulating lactate and its metabolism in various diseases is lacking. This review outlines the sources and clearance of lactate, as well as its roles in cancer, liver fibrosis, sepsis, ischemic stroke, myocardial infarction, and acute kidney injury, and summarizes the effects of small molecules on lactate regulation. It aims to provide a reference and direction for future research.
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Affiliation(s)
- Jin Liu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Feng Zhou
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yang Tang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Linghui Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Ling Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China
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9
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Hu Y, Liu W, Fang W, Dong Y, Zhang H, Luo Q. Tumor energy metabolism: implications for therapeutic targets. MOLECULAR BIOMEDICINE 2024; 5:63. [PMID: 39609317 PMCID: PMC11604893 DOI: 10.1186/s43556-024-00229-4] [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: 07/23/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 11/30/2024] Open
Abstract
Tumor energy metabolism plays a crucial role in the occurrence, progression, and drug resistance of tumors. The study of tumor energy metabolism has gradually become an emerging field of tumor treatment. Recent studies have shown that epigenetic regulation is closely linked to tumor energy metabolism, influencing the metabolic remodeling and biological traits of tumor cells. This review focuses on the primary pathways of tumor energy metabolism and explores therapeutic strategies to target these pathways. It covers key areas such as glycolysis, the Warburg effect, mitochondrial function, oxidative phosphorylation, and the metabolic adaptability of tumors. Additionally, this article examines the role of the epigenetic regulator SWI/SNF complex in tumor metabolism, specifically its interactions with glucose, lipids, and amino acids. Summarizing therapeutic strategies aimed at these metabolic pathways, including inhibitors of glycolysis, mitochondrial-targeted drugs, exploitation of metabolic vulnerabilities, and recent developments related to SWI/SNF complexes as potential targets. The clinical significance, challenges, and future directions of tumor metabolism research are discussed, including strategies to overcome drug resistance, the potential of combination therapy, and the application of new technologies.
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Affiliation(s)
- Youwu Hu
- The Public Experimental Center of Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563003, China
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Wanqing Liu
- The Public Experimental Center of Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563003, China
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - WanDi Fang
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yudi Dong
- The Public Experimental Center of Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563003, China
| | - Hong Zhang
- Department of Pathology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qing Luo
- The Public Experimental Center of Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi, Guizhou, 563003, China.
- Guizhou Provincial Key Laboratory of Cell Engineering, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
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10
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Komza M, Khatun J, Gelles JD, Trotta AP, Abraham-Enachescu I, Henao J, Elsaadi A, Kotini AG, Clementelli C, Arandela J, El Ghaity-Beckley S, Barua A, Chen Y, Marcellino BK, Papapetrou EP, Poyurovsky MV, Chipuk JE. Metabolic Adaptations To Acute Glucose Uptake Inhibition Converge Upon Mitochondrial Respiration For Leukemia Cell Survival. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.20.624567. [PMID: 39713344 PMCID: PMC11661232 DOI: 10.1101/2024.11.20.624567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.
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11
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Chiu CF, Guerrero JJG, Regalado RRH, Zhou J, Notarte KI, Lu YW, Encarnacion PC, Carles CDD, Octavo EM, Limbaroc DCI, Saengboonmee C, Huang SY. Insights into Metabolic Reprogramming in Tumor Evolution and Therapy. Cancers (Basel) 2024; 16:3513. [PMID: 39456607 PMCID: PMC11506062 DOI: 10.3390/cancers16203513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/09/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research.
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Affiliation(s)
- Ching-Feng Chiu
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110301, Taiwan; (J.J.G.G.); (Y.-W.L.); (P.C.E.)
- Taipei Medical University Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110301, Taiwan
| | - Jonathan Jaime G. Guerrero
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110301, Taiwan; (J.J.G.G.); (Y.-W.L.); (P.C.E.)
- College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (C.D.D.C.); (E.M.O.); (D.C.I.L.)
- College of Public Health, University of the Philippines Manila, Manila 1000, Philippines
| | - Ric Ryan H. Regalado
- National Institute of Molecular Biology and Biotechnology, College of Science, University of the Philippines Diliman, Quezon City 1101, Philippines;
| | - Jiayan Zhou
- Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA;
| | - Kin Israel Notarte
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA;
| | - Yu-Wei Lu
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110301, Taiwan; (J.J.G.G.); (Y.-W.L.); (P.C.E.)
| | - Paolo C. Encarnacion
- Graduate Institute of Metabolism and Obesity Sciences, Taipei Medical University, Taipei 110301, Taiwan; (J.J.G.G.); (Y.-W.L.); (P.C.E.)
- College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (C.D.D.C.); (E.M.O.); (D.C.I.L.)
- College of Public Health, University of the Philippines Manila, Manila 1000, Philippines
- Department of Industrial Engineering and Management, Yuan Ze University, 135 Yuan-Tung Road, Chung-Li 32003, Taiwan
| | - Cidne Danielle D. Carles
- College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (C.D.D.C.); (E.M.O.); (D.C.I.L.)
- College of Public Health, University of the Philippines Manila, Manila 1000, Philippines
| | - Edrian M. Octavo
- College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (C.D.D.C.); (E.M.O.); (D.C.I.L.)
| | - Dan Christopher I. Limbaroc
- College of Medicine, University of the Philippines Manila, Manila 1000, Philippines; (C.D.D.C.); (E.M.O.); (D.C.I.L.)
- College of Public Health, University of the Philippines Manila, Manila 1000, Philippines
| | - Charupong Saengboonmee
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Shih-Yi Huang
- School of Nutrition and Health Sciences, Taipei Medical University, Taipei 110301, Taiwan
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12
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Kooshan Z, Cárdenas-Piedra L, Clements J, Batra J. Glycolysis, the sweet appetite of the tumor microenvironment. Cancer Lett 2024; 600:217156. [PMID: 39127341 DOI: 10.1016/j.canlet.2024.217156] [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: 02/14/2024] [Revised: 07/17/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.
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Affiliation(s)
- Zeinab Kooshan
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Lilibeth Cárdenas-Piedra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia
| | - Judith Clements
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia.
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13
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Kumar A, Gupta AK, Singh PK. Novel perspective of therapeutic modules to overcome motor and nonmotor symptoms in Parkinson's disease. AIMS Neurosci 2024; 11:312-340. [PMID: 39431269 PMCID: PMC11486614 DOI: 10.3934/neuroscience.2024020] [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: 05/18/2024] [Revised: 08/21/2024] [Accepted: 08/28/2024] [Indexed: 10/22/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder that involves the loss of dopaminergic neurons, which leads to motor and non-motor symptoms that have a significant impact. The pathophysiology of PD is complex and involves environmental and genetic factors that contribute to alpha-synuclein aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The current treatments of PD primarily focus on symptom management and have limitations in addressing disease progression and non-motor symptoms. Epidemiological data indicates a rise in PD cases worldwide, which highlights the need for effective treatments. Pathophysiological insights point out the involvement of various factors in PD progression, such as dopamine dysregulation, genetic mutations, oxidative stress, mitochondrial damage, alpha-synuclein aggregation, and neuroinflammation. Although current treatments, which include dopamine precursors, monoamine oxidase (MAO) inhibitors, and non-dopaminergic drugs, can alleviate motor symptoms, they are not effective in preventing disease progression or managing non-motor symptoms. Additionally, they can lead to adverse effects and become less effective over time. Novel therapeutic approaches, including cell-based therapies, gene therapies, targeted drug delivery therapies, and magnetic field therapies, are promising in improving symptom management and providing personalized treatment. Additionally, emerging therapies that target alpha-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation may have potential disease-modifying effects. To sum up, for dealing with the multiple aspects of PD, there is a great need to come up with new and creative therapeutic approaches that not only relieve symptoms, but also prevent the progression of disease and non-motor symptoms. The progress made in comprehending the underlying mechanisms of PD provides optimism for developing successful treatments that can enhance the outcomes and quality of life.
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Affiliation(s)
- Anmol Kumar
- School of Pharmaceutical Science (formerly University Institute of Pharmacy), Chhatrapati Shahu Ji Maharaj University (formerly Kanpur University), Kanpur 208024, India
| | - Ajay Kumar Gupta
- School of Pharmaceutical Science (formerly University Institute of Pharmacy), Chhatrapati Shahu Ji Maharaj University (formerly Kanpur University), Kanpur 208024, India
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14
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Bi C, Huang Y, Ali R, Wang F, Yang X, Bouska A, Xu L, Hao X, Lunning MA, Chan WC, Iqbal J, Weisenburger DD, Vose JM, Fu K. MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications. Haematologica 2024; 109:2810-2821. [PMID: 38546691 PMCID: PMC11367202 DOI: 10.3324/haematol.2023.283811] [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: 08/07/2023] [Accepted: 03/18/2024] [Indexed: 09/03/2024] Open
Abstract
The current clinical management of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the prognostic index of NK cells lymphoma with Epstein-Barr virus (PINK-E) prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA sequencing used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-sequencing data upon MYC knockdown with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.
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Affiliation(s)
- Chengfeng Bi
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.
| | - Yuhua Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong
| | - Roshia Ali
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Molecular Diagnosis, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong
| | - Xia Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong
| | - Alyssa Bouska
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Lu Xu
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Department of Hematology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan
| | - Xinbao Hao
- State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing
| | - Matthew A Lunning
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Wing C Chan
- Department of Pathology, City of Hope National Medical Center, Duarte, CA
| | - Javeed Iqbal
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Dennis D Weisenburger
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
| | - Julie M Vose
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
| | - Kai Fu
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
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15
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Keuters MH, Keksa-Goldsteine V, Rõlova T, Jaronen M, Kettunen P, Halkoluoto A, Goldsteins G, Koistinaho J, Dhungana H. Benserazide is neuroprotective and improves functional recovery after experimental ischemic stroke by altering the immune response. Sci Rep 2024; 14:17949. [PMID: 39095453 PMCID: PMC11297251 DOI: 10.1038/s41598-024-68986-4] [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: 02/15/2024] [Accepted: 07/30/2024] [Indexed: 08/04/2024] Open
Abstract
Stroke is a leading cause of permanent disability worldwide. Despite intensive research over the last decades, key anti-inflammatory strategies that have proven beneficial in pre-clinical animal models have often failed in translation. The importance of neutrophils as pro- and anti-inflammatory peripheral immune cells has often been overlooked in ischemic stroke. However, neutrophils rapidly infiltrate into the brain parenchyma after stroke and secrete an array of pro-inflammatory factors including reactive oxygen species, proteases, cytokines, and chemokines exacerbating damage. In this study, we demonstrate the neuroprotective and anti-inflammatory effect of benserazide, a clinically used DOPA decarboxylase inhibitor, using both in vitro models of inflammation and in vivo mouse models of focal cerebral ischemia. Benserazide significantly attenuated PMA-induced NETosis in isolated human neutrophils. Furthermore, benserazide was able to protect both SH-SY5Y and iPSC-derived human cortical neurons when challenged with activated neutrophils demonstrating the clinical relevance of this study. Additional in vitro data suggest the ability of benserazide to polarize macrophages towards M2-phenotypes following LPS stimulation. Neuroprotective effects of benserazide are further demonstrated by in vivo studies where peripheral administration of benserazide significantly attenuated neutrophil infiltration into the brain, altered microglia/macrophage phenotypes, and improved the behavioral outcome post-stroke. Overall, our data suggest that benserazide could serve as a drug candidate for the treatment of ischemic stroke. The importance of our results for future clinical trials is further underlined as benserazide has been approved by the European Medicines Agency as a safe and effective treatment in Parkinson's disease when combined with levodopa.
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Affiliation(s)
- Meike Hedwig Keuters
- Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Velta Keksa-Goldsteine
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Taisia Rõlova
- Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland
| | - Merja Jaronen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Pinja Kettunen
- Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland
| | - Aurora Halkoluoto
- Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland
| | - Gundars Goldsteins
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jari Koistinaho
- Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
| | - Hiramani Dhungana
- Neuroscience Center, HiLIFE, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
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16
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Ni X, Lu CP, Xu GQ, Ma JJ. Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy. Acta Pharmacol Sin 2024; 45:1533-1555. [PMID: 38622288 PMCID: PMC11272797 DOI: 10.1038/s41401-024-01264-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 03/08/2024] [Indexed: 04/17/2024]
Abstract
Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.
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Affiliation(s)
- Xuan Ni
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China
| | - Cheng-Piao Lu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China
| | - Guo-Qiang Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, 215123, China.
- Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, 215123, China.
| | - Jing-Jing Ma
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, 215123, China.
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17
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Yoshikawa T, Endo K, Moriyama-Kita M, Ueno T, Nakanishi Y, Dochi H, Uno D, Kondo S, Yoshizaki T. Association of 18F- fluorodeoxyglucose uptake with the expression of metabolism-related molecules in papillary thyroid cancer. Auris Nasus Larynx 2024; 51:696-702. [PMID: 38733874 DOI: 10.1016/j.anl.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/28/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024]
Abstract
OBJECTIVES 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) is a diagnostic imaging method that is based on the Warburg effect, which is the increased uptake of glucose through aerobic glycolysis in cancer cells. The diagnostic value of 18F-FDG-PET/CT for thyroid cancer is controversial. However, uptake of 18F-FDG and the corresponding maximum standardized uptake value (SUVmax) is expected to reflect the metabolic status of cancer cells. In the present study, we sought to determine the relationship between 18F-FDG uptake and tumor metabolism- associated factors. METHODS This was a single-center retrospective study. In the present study, SUVmax was compared with the expression of hexokinase 2 (HK2), glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF), and glutaminase 1 (GLS1) in 41 patients with thyroid cancer. RESULTS GLS1 expression was found to be moderately correlated with SUVmax (p < 0.001, r = 0.51), whereas HK2 and VEGF expression were weakly correlated (p = 0.011, r = 0.28, p = 0.008, r = 0.29, respectively) and GLUT1 did not correlate with SUVmax (p = 0.62, r = 0.06). CONCLUSION Our findings suggest 18F-FDG PET/CT reflects GLS1 expression in thyroid cancer and could be used to select suitable candidates for GLS1 inhibitor treatment.
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Affiliation(s)
- Tomomi Yoshikawa
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan.
| | - Kazuhira Endo
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Makiko Moriyama-Kita
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takayoshi Ueno
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yosuke Nakanishi
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Hirotomo Dochi
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Daisuke Uno
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Satoru Kondo
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Tomokazu Yoshizaki
- Department of Otolaryngology-Head and Neck Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
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18
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Reed EK, Smith KA. Using our understanding of interactions between helminth metabolism and host immunity to target worm survival. Trends Parasitol 2024; 40:549-561. [PMID: 38853079 DOI: 10.1016/j.pt.2024.05.006] [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: 01/29/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 06/11/2024]
Abstract
Helminths can adapt to environmental conditions in the host, utilising anaerobic processes like fermentation and malate dismutation to produce energy from carbohydrate. Although targeting carbohydrate metabolism is an established therapeutic strategy to combat helminth infection, questions remain over the metabolic pathways they employ as adults to survive and evade host immunity. Helminths also use amino acid, polyunsaturated fatty acid (PUFA), and cholesterol metabolism, a possible strategy favouring the production of immunomodulatory compounds that may influence survival in the host. Here, we discuss the significance of these differing metabolic pathways and whether targeting of helminth metabolic pathways may allow for the development of novel anthelmintics.
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Affiliation(s)
- Ella K Reed
- Cardiff School of Biosciences, Cardiff University, Cardiff, UK
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19
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Han J, Dong H, Zhu T, Wei Q, Wang Y, Wang Y, Lv Y, Mu H, Huang S, Zeng K, Xu J, Ding J. Biochemical hallmarks-targeting antineoplastic nanotherapeutics. Bioact Mater 2024; 36:427-454. [PMID: 39044728 PMCID: PMC11263727 DOI: 10.1016/j.bioactmat.2024.05.042] [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: 02/20/2024] [Revised: 05/18/2024] [Accepted: 05/27/2024] [Indexed: 07/25/2024] Open
Abstract
Tumor microenvironments (TMEs) have received increasing attention in recent years as they play pivotal roles in tumorigenesis, progression, metastases, and resistance to the traditional modalities of cancer therapy like chemotherapy. With the rapid development of nanotechnology, effective antineoplastic nanotherapeutics targeting the aberrant hallmarks of TMEs have been proposed. The appropriate design and fabrication endow nanomedicines with the abilities for active targeting, TMEs-responsiveness, and optimization of physicochemical properties of tumors, thereby overcoming transport barriers and significantly improving antineoplastic therapeutic benefits. This review begins with the origins and characteristics of TMEs and discusses the latest strategies for modulating the TMEs by focusing on the regulation of biochemical microenvironments, such as tumor acidosis, hypoxia, and dysregulated metabolism. Finally, this review summarizes the challenges in the development of smart anti-cancer nanotherapeutics for TME modulation and examines the promising strategies for combination therapies with traditional treatments for further clinical translation.
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Affiliation(s)
- Jing Han
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - He Dong
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Tianyi Zhu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Qi Wei
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
| | - Yongheng Wang
- Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA
| | - Yun Wang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Yu Lv
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Haoran Mu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Shandeng Huang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Ke Zeng
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Jing Xu
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Bone Tumor Institution, 100 Haining Street, Shanghai, 200080, PR China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, PR China
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20
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Zhao W, Feng S, Wang J, Zhang Z, Chen L, Jiang L, Li M, Wang T. Benserazide, a cystathionine beta-synthase (CBS) inhibitor, potentially enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and the HIF1-α/VEGF pathway. Front Pharmacol 2024; 15:1404532. [PMID: 38828455 PMCID: PMC11143879 DOI: 10.3389/fphar.2024.1404532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 05/06/2024] [Indexed: 06/05/2024] Open
Abstract
Cancer targeted therapy is essential to minimize damage to normal cells and improve treatment outcomes. The elevated activity of Cystathionine beta-synthase (CBS), an enzyme responsible for producing endogenous hydrogen sulfide (H2S), plays a significant role in promoting tumor growth, invasiveness, and metastatic potential. Consequently, the selective inhibition of CBS could represent a promising therapeutic strategy for cancer. Currently, there is much interest in combining paclitaxel with other drugs for cancer treatment. This study aimed to investigate the efficacy of combining benserazide, a CBS inhibitor, with paclitaxel in treating tumors. Firstly, we demonstrated CBS is indeed involved in the progression of multiple cancers. Then it was observed that the total binding free energy between the protein and the small molecule is -98.241 kJ/mol. The release of H2S in the group treated with 100 μM benserazide was reduced by approximately 90% compared to the negative control, and the thermal denaturation curve of the complex protein shifted to the right, suggesting that benserazide binds to and blocks the CBS protein. Next, it was found that compared to paclitaxel monotherapy, the combination of benserazide with paclitaxel demonstrated stronger antitumor activity in KYSE450, A549, and HCT8 cells, accompanied by reduced cell viability, cell migration and invasion, as well as diminished angiogenic and lymphangiogenic capabilities. In vivo studies showed that the combined administration of benserazide and paclitaxel significantly reduced the volume and weight of axillary lymph nodes in comparison to the control group and single administration group. Further mechanistic studies revealed that the combination of benserazide and paclitaxel significantly suppressed the S-sulfhydration of SIRT1 protein, thereby inhibiting the expression of SIRT1 protein and activating SIRT1 downstream Notch1/Hes1 signaling pathway in KYSE450, A549, and HCT8 cells. Meanwhile, we observed that benserazide combined with paclitaxel induced a more significant downregulation of HIF-1α, VEGF-A, VEGF-C, and VEGF-D proteins expression levels in KYSE450, A549, and HCT8 cells compared to paclitaxel alone. These findings indicated that benserazide enhances the anticancer effects of paclitaxel via inhibiting the S-sulfhydration of SIRT1 and down-regulating HIF-1α/VEGF signaling pathway. This study suggests that benserazide may have potential as a chemosensitizer in cancer treatment.
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Affiliation(s)
| | | | | | | | | | | | - Ming Li
- School of Pharmacy, Henan University, Kaifeng, Henan, China
| | - Tianxiao Wang
- School of Pharmacy, Henan University, Kaifeng, Henan, China
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21
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He Y, Luo Y, Huang L, Zhang D, Hou H, Liang Y, Deng S, Zhang P, Liang S. Novel inhibitors targeting the PGK1 metabolic enzyme in glycolysis exhibit effective antitumor activity against kidney renal clear cell carcinoma in vitro and in vivo. Eur J Med Chem 2024; 267:116209. [PMID: 38354523 DOI: 10.1016/j.ejmech.2024.116209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/29/2024] [Accepted: 01/31/2024] [Indexed: 02/16/2024]
Abstract
Our previous research has revealed phosphoglycerate kinase 1 (PGK1) enhances tumorigenesis and sorafenib resistance of kidney renal clear cell carcinoma (KIRC) by regulating glycolysis, so that PGK1 is a promising drug target. Herein we performed structure-based virtual screening and series of anticancer pharmaceutical experiments in vitro and in vivo to identify novel small-molecule PGK1-targeted compounds. As results, the compounds CHR-6494 and Z57346765 were screened and confirmed to specifically bind to PGK1 and significantly reduced the metabolic enzyme activity of PGK1 in glycolysis, which inhibited KIRC cell proliferation in a dose-dependent manner. While CHR-6494 showed greater anti-KIRC efficacy and fewer side effects than Z57346765 on nude mouse xenograft model. Mechanistically, CHR-9464 impeded glycolysis by decreasing the metabolic enzyme activity of PGK1 and suppressed histone H3T3 phosphorylation to inhibit KIRC cell proliferation. Z57346765 induced expression changes of genes related to cell metabolism, DNA replication and cell cycle. Overall, we screened two novel PGK1 inhibitors, CHR-6494 and Z57346765, for the first time and discovered their potent anti-KIRC effects by suppressing PGK1 metabolic enzyme activity in glycolysis.
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Affiliation(s)
- Yu He
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Yinheng Luo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Lan Huang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Dan Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Huijin Hou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Yue Liang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Shi Deng
- Department of Urinary Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, PR China.
| | - Peng Zhang
- Department of Urinary Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, PR China.
| | - Shufang Liang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
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22
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Katayama H, Fujimura A, Huang R, Otani Y, Itano T, Fujiwara T, Kunisada T, Nakata E, Ozaki T. Role of catecholamine synthases in the maintenance of cancer stem-like cells in malignant peripheral nerve sheath tumors. Cancer Sci 2024; 115:871-882. [PMID: 38279513 PMCID: PMC10921001 DOI: 10.1111/cas.16077] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 12/08/2023] [Accepted: 12/30/2023] [Indexed: 01/28/2024] Open
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are malignant tumors that are derived from Schwann cell lineage around peripheral nerves. As in many other cancer types, cancer stem cells (CSCs) have been identified in MPNSTs, and they are considered the cause of treatment resistance, recurrence, and metastasis. As an element defining the cancer stemness of MPNSTs, we previously reported a molecular mechanism by which exogenous adrenaline activates a core cancer stemness factor, YAP/TAZ, through β2 adrenoceptor (ADRB2). In this study, we found that MPNST cells express catecholamine synthases and that these enzymes are essential for maintaining cancer stemness, such as the ability to self-renew and maintain an undifferentiated state. Through gene knockdown and inhibition of these enzymes, we confirmed that catecholamines are indeed synthesized in MPNST cells. The results confirmed that catecholamine synthase knockdown in MPNST cells reduces the activity of YAP/TAZ. These data suggest that a mechanism of YAP/TAZ activation by de novo synthesized adrenaline, as well as exogenous adrenaline, may exist in the maintenance of cancer stemness of MPNST cells. This mechanism not only helps to understand the pathology of MPNST, but could also contribute to the development of therapeutic strategies for MPNST.
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Affiliation(s)
- Haruyoshi Katayama
- Department of Orthopedic SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Atsushi Fujimura
- Department of Cellular PhysiologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
- Neutron Therapy Research CenterOkayama UniversityOkayamaJapan
| | - Rongsheng Huang
- Department of Trauma OrthopedicsThe Second Hospital of Dalian Medical UniversityDalianChina
| | - Yusuke Otani
- Department of General Thoracic Surgery and Breast and Endocrinological SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Takuto Itano
- Department of Orthopedic SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Tomohiro Fujiwara
- Department of Orthopedic SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Toshiyuki Kunisada
- Department of Orthopedic SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Eiji Nakata
- Department of Orthopedic SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
| | - Toshifumi Ozaki
- Department of Orthopedic SurgeryOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
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23
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Juszczak K, Szczepankiewicz W, Walczak K. Synthesis and Primary Activity Assay of Novel Benitrobenrazide and Benserazide Derivatives. Molecules 2024; 29:629. [PMID: 38338374 PMCID: PMC10856005 DOI: 10.3390/molecules29030629] [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: 01/02/2024] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Schiff bases attract research interest due to their applications in chemical synthesis and medicinal chemistry. In recent years, benitrobenrazide and benserazide containing imine moiety have been synthesized and characterized as promising inhibitors of hexokinase 2 (HK2), an enzyme overexpressed in most cancer cells. Benserazide and benitrobenrazide possess a common structural fragment, a 2,3,4-trihydroxybenzaldehyde moiety connected through a hydrazone or hydrazine linker acylated on an N' nitrogen atom by serine or a 4-nitrobenzoic acid fragment. To avoid the presence of a toxicophoric nitro group in the benitrobenrazide molecule, we introduced common pharmacophores such as 4-fluorophenyl or 4-aminophenyl substituents. Modification of benserazide requires the introduction of other endogenous amino acids instead of serine. Herein, we report the synthesis of benitrobenrazide and benserazide analogues and preliminary results of inhibitory activity against HK2 evoked by these structural changes. The derivatives contain a fluorine atom or amino group instead of a nitro group in BNB and exhibit the most potent inhibitory effects against HK2 at a concentration of 1 µM, with HK2 inhibition rates of 60% and 54%, respectively.
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Affiliation(s)
| | | | - Krzysztof Walczak
- Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry, Silesian University of Technology, 44-100 Gliwice, Poland; (K.J.); (W.S.)
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24
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Chen J, Li G, Sun D, Li H, Chen L. Research progress of hexokinase 2 in inflammatory-related diseases and its inhibitors. Eur J Med Chem 2024; 264:115986. [PMID: 38011767 DOI: 10.1016/j.ejmech.2023.115986] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/14/2023] [Accepted: 11/19/2023] [Indexed: 11/29/2023]
Abstract
Hexokinase 2 (HK2) is a crucial enzyme involved in glycolysis, which converts glucose into glucose-6-phosphate and plays a significant role in glucose metabolism. HK2 can mediate glycolysis, which is linked to the release of inflammatory factors. The over-expression of HK2 increases the production of pro-inflammatory cytokines, exacerbating the inflammatory reaction. Consequently, HK2 is closely linked to various inflammatory-related diseases affecting multiple systems, including the digestive, nervous, circulatory, respiratory, reproductive systems, as well as rheumatoid arthritis. HK2 is regarded as a novel therapeutic target for inflammatory-related diseases, and this article provides a comprehensive review of its roles in these conditions. Furthermore, the development of potent HK2 inhibitors has garnered significant attention in recent years. Therefore, this review also presents a summary of potential HK2 inhibitors, offering promising prospects for the treatment of inflammatory-related diseases in the future.
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Affiliation(s)
- Jinxia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Guirong Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China
| | - Dejuan Sun
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
| | - Hua Li
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China; Institute of Structural Pharmacology & TCM Chemical Biology, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
| | - Lixia Chen
- Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China.
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25
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Zhang S, Zhang X, Yang H, Liang T, Bai X. Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity. Biochim Biophys Acta Rev Cancer 2024; 1879:189022. [PMID: 37993001 DOI: 10.1016/j.bbcan.2023.189022] [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: 07/14/2023] [Revised: 09/11/2023] [Accepted: 10/08/2023] [Indexed: 11/24/2023]
Abstract
Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.
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Affiliation(s)
- Sirui Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Hanshen Yang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China.
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou 310058, Zhejiang, China.
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26
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Liu B, Lu Y, Taledaohan A, Qiao S, Li Q, Wang Y. The Promoting Role of HK II in Tumor Development and the Research Progress of Its Inhibitors. Molecules 2023; 29:75. [PMID: 38202657 PMCID: PMC10779805 DOI: 10.3390/molecules29010075] [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: 10/26/2023] [Revised: 12/09/2023] [Accepted: 12/15/2023] [Indexed: 01/12/2024] Open
Abstract
Increased glycolysis is a key characteristic of malignant cells that contributes to their high proliferation rates and ability to develop drug resistance. The glycolysis rate-limiting enzyme hexokinase II (HK II) is overexpressed in most tumor cells and significantly affects tumor development. This paper examines the structure of HK II and the specific biological factors that influence its role in tumor development, as well as the potential of HK II inhibitors in antitumor therapy. Furthermore, we identify and discuss the inhibitors of HK II that have been reported in the literature.
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Affiliation(s)
- Bingru Liu
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China; (B.L.); (Y.L.); (A.T.)
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Yu Lu
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China; (B.L.); (Y.L.); (A.T.)
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
- Department of Core Facility Center, Capital Medical University, Beijing 100069, China
| | - Ayijiang Taledaohan
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China; (B.L.); (Y.L.); (A.T.)
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
| | - Shi Qiao
- Civil Aviation Medical Center, Civil Aviation Administration of China, Beijing 100123, China;
| | - Qingyan Li
- Civil Aviation Medical Center, Civil Aviation Administration of China, Beijing 100123, China;
| | - Yuji Wang
- Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, China; (B.L.); (Y.L.); (A.T.)
- Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China
- Department of Core Facility Center, Capital Medical University, Beijing 100069, China
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27
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Guo Y, Lu X, Zhou Y, Chen WH, Tam KY. Combined inhibition of pyruvate dehydrogenase kinase 1 and hexokinase 2 induces apoptsis in non-small cell lung cancer cell models. Exp Cell Res 2023; 433:113830. [PMID: 37913974 DOI: 10.1016/j.yexcr.2023.113830] [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: 06/20/2023] [Revised: 09/25/2023] [Accepted: 10/23/2023] [Indexed: 11/03/2023]
Abstract
Many cancer cells exhibit enhanced glycolysis, which is seen as one of the hallmark metabolic alterations, known as Warburg effect. Substantial evidence shows that upregulated glycolytic enzymes are often linked to malignant growth. Using glycolytic inhibitors for anticancer treatment has become appealing in recent years for therapeutic intervention in cancers with highly glycolytic characteristic, including non-small cell lung cancer (NSCLC). In this work, we studied the anticancer effects and the underlying mechanisms of combination of benzerazide hydrocholoride (Benz), a hexokinase 2 (HK2) inhibitor and 64, a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor, in several NSCLC cell lines. We found that combination of Benz and 64 exhibited strong synergistic anticancer effects in NCI-H1975, HCC827, NCI-H1299 and SK-LU-1 cell lines. With this combination treatment, we observed changes of certain mechanistic determinants associated with metabolic stress caused by glycolysis restriction, such as mitochondrial membrane potential depolarization, overproduction of reactive oxygen species [1], activation of AMPK and down-regulation of mTOR, which contributed to enhanced apoptosis. Moreover, Benz and 64 together significantly suppressed the tumor growth in HCC827 cell mouse xenograft model. Taken together, our study may suggest that combined inhibition of HK2 and PDK1 using Benz and 64 could be a viable anticancer strategy for NSCLC.
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Affiliation(s)
- Yizhen Guo
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Xianchen Lu
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong, 529020, PR China
| | - Yan Zhou
- Faculty of Health Sciences, University of Macau, Taipa, Macau
| | - Wen-Hua Chen
- School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong, 529020, PR China.
| | - Kin Yip Tam
- Faculty of Health Sciences, University of Macau, Taipa, Macau.
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28
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Zhang B, Zhang W, He Y, Ma X, Li M, Jiang Q, Loor JJ, Lv X, Yang W, Xu C. Store-operated Ca 2+ entry-sensitive glycolysis regulates neutrophil adhesion and phagocytosis in dairy cows with subclinical hypocalcemia. J Dairy Sci 2023; 106:7131-7146. [PMID: 37164848 DOI: 10.3168/jds.2022-22709] [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: 08/29/2022] [Accepted: 04/06/2023] [Indexed: 05/12/2023]
Abstract
Hypocalcemia in dairy cows is associated with a decrease of neutrophil adhesion and phagocytosis, an effect driven partly by changes in the expression of store-operated Ca2+ entry (SOCE)-related molecules. It is well established in nonruminants that neutrophils obtain the energy required for immune function through glycolysis. Whether glycolysis plays a role in the acquisition of energy by neutrophils during hypocalcemia in dairy cows is unknown. To address this relationship, we performed a cohort study and then a clinical trial. Neutrophils were isolated at 2 d postcalving from lactating Holstein dairy cows (average 2.83 ± 0.42 lactations, n = 6) diagnosed as clinically healthy (CON) or with plasma concentrations of Ca2+ <2.0 mmol/L as a criterion for diagnosing subclinical hypocalcemia (HYP, average 2.83 ± 0.42 lactations, n = 6). In the first experiment, neutrophils were isolated from blood of CON and HYP cows and used to analyze aspects of adhesion and phagocytosis function through quantitative reverse-transcription PCR along with confocal laser scanning microscopy, mRNA expression of the glycolysis-related gene hexokinase 2 (HKII), and components of the SOCE moiety ORAI calcium release-activated calcium modulator 1 (ORAI1, ORAI2, ORAI3, stromal interaction molecule 1 [STIM1], and STIM2). Results showed that adhesion and phagocytosis function were reduced in HYP cows. The mRNA expression of adhesion-related syndecan-4 (SDC4), integrin β9 (ITGA9), and integrin β3 (ITGB3) and phagocytosis-related molecules complement component 1 R subcomponent (C1R), CD36, tubulinß1 (TUBB1) were significantly decreased in the HYP group. In the second experiment, to address how glycolysis affects neutrophil adhesion and phagocytosis, neutrophils isolated from CON and HYP cows were treated with 2 μM HKII inhibitor benserazide-d3 or 1 μM fructose-bisphosphatase 1 (FBP1) inhibitor MB05032 for 1 h. Results revealed that the HKII inhibitor benserazide-d3 reduced phagocytosis and the mRNA abundance of ITGA9, and CD36 in the HYP group. The FBP1 inhibitor MB05032 increased adhesion and phagocytosis and increased mRNA abundance of HKII, ITGA9, and CD36 in the HYP group. Finally, to investigate the mechanism whereby SOCE-sensitive glycolysis affects neutrophil adhesion and phagocytosis, isolated neutrophils were treated with 1 μM SOCE activator thapsigargin or 50 μM inhibitor 2-APB for 1 h. Results showed that thapsigargin increased mRNA abundance of HKII, ITGA9, and CD36, and increased adhesion and phagocytosis in the HYP group. In contrast, 2-APB decreased mRNA abundance of HKII and both adhesion and phagocytosis of neutrophils in the CON group. Overall, the data indicated that SOCE-sensitive intracellular Ca2+ levels affect glycolysis and help regulate adhesion and phagocytosis of neutrophils during hypocalcemia in dairy cows.
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Affiliation(s)
- Bingbing Zhang
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Wei Zhang
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Yuxin He
- College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Xinru Ma
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Ming Li
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Qianming Jiang
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801
| | - Juan J Loor
- Mammalian NutriPhysioGenomics, Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801
| | - Xinquan Lv
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Wei Yang
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China
| | - Chuang Xu
- College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China; College of Veterinary Medicine, China Agricultural University, Beijing 100000, China.
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Pawar VA, Tyagi A, Verma C, Sharma KP, Ansari S, Mani I, Srivastva SK, Shukla PK, Kumar A, Kumar V. Unlocking therapeutic potential: integration of drug repurposing and immunotherapy for various disease targeting. Am J Transl Res 2023; 15:4984-5006. [PMID: 37692967 PMCID: PMC10492070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023]
Abstract
Drug repurposing, also known as drug repositioning, entails the application of pre-approved or formerly assessed drugs having potentially functional therapeutic amalgams for curing various disorders or disease conditions distinctive from their original remedial indication. It has surfaced as a substitute for the development of drugs for treating cancer, cardiovascular diseases, neurodegenerative disorders, and various infectious diseases like Covid-19. Although the earlier lines of findings in this area were serendipitous, recent advancements are based on patient centered approaches following systematic, translational, drug targeting practices that explore pathophysiological ailment mechanisms. The presence of definite information and numerous records with respect to beneficial properties, harmfulness, and pharmacologic characteristics of repurposed drugs increase the chances of approval in the clinical trial stages. The last few years have showcased the successful emergence of repurposed drug immunotherapy in treating various diseases. In this light, the present review emphasises on incorporation of drug repositioning with Immunotherapy targeted for several disorders.
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Affiliation(s)
| | - Anuradha Tyagi
- Department of cBRN, Institute of Nuclear Medicine and Allied ScienceDelhi 110054, India
| | - Chaitenya Verma
- Department of Pathology, Wexner Medical Center, Ohio State UniversityColumbus, Ohio 43201, USA
| | - Kanti Prakash Sharma
- Department of Nutrition Biology, Central University of HaryanaMahendragarh 123029, India
| | - Sekhu Ansari
- Division of Pathology, Cincinnati Children’s Hospital Medical CenterCincinnati, Ohio 45229, USA
| | - Indra Mani
- Department of Microbiology, Gargi College, University of DelhiNew Delhi 110049, India
| | | | - Pradeep Kumar Shukla
- Department of Biological Sciences, Faculty of Science, Sam Higginbottom University of Agriculture, Technology of SciencePrayagraj 211007, UP, India
| | - Antresh Kumar
- Department of Biochemistry, Central University of HaryanaMahendergarh 123031, Haryana, India
| | - Vinay Kumar
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical CenterColumbus, Ohio 43210, USA
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Liu D, Wang H, Li X, Liu J, Zhang Y, Hu J. Small molecule inhibitors for cancer metabolism: promising prospects to be explored. J Cancer Res Clin Oncol 2023; 149:8051-8076. [PMID: 37002510 DOI: 10.1007/s00432-022-04501-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 11/28/2022] [Indexed: 04/03/2023]
Abstract
BACKGROUND Abnormal metabolism is the main hallmark of cancer, and cancer metabolism plays an important role in tumorigenesis, metastasis, and drug resistance. Therefore, studying the changes of tumor metabolic pathways is beneficial to find targets for the treatment of cancer diseases. The success of metabolism-targeted chemotherapy suggests that cancer metabolism research will provide potential new targets for the treatment of malignant tumors. PURPOSE The aim of this study was to systemically review recent research findings on targeted inhibitors of tumor metabolism. In addition, we summarized new insights into tumor metabolic reprogramming and discussed how to guide the exploration of new strategies for cancer-targeted therapy. CONCLUSION Cancer cells have shown various altered metabolic pathways, providing sufficient fuel for their survival. The combination of these pathways is considered to be a more useful method for screening multilateral pathways. Better understanding of the clinical research progress of small molecule inhibitors of potential targets of tumor metabolism will help to explore more effective cancer treatment strategies.
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Affiliation(s)
- Dan Liu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - HongPing Wang
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - XingXing Li
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - JiFang Liu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - YanLing Zhang
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China
| | - Jing Hu
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, 400038, China.
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31
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You M, Xie Z, Zhang N, Zhang Y, Xiao D, Liu S, Zhuang W, Li L, Tao Y. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8:196. [PMID: 37164974 PMCID: PMC10172373 DOI: 10.1038/s41392-023-01442-3] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/12/2023] Open
Abstract
A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
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Affiliation(s)
- Mengshu You
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Zhuolin Xie
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Nan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Yixuan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Wei Zhuang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People's Republic of China.
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong.
| | - Yongguang Tao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China.
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China.
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China.
- Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, 410011, Changsha, China.
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Nong S, Han X, Xiang Y, Qian Y, Wei Y, Zhang T, Tian K, Shen K, Yang J, Ma X. Metabolic reprogramming in cancer: Mechanisms and therapeutics. MedComm (Beijing) 2023; 4:e218. [PMID: 36994237 PMCID: PMC10041388 DOI: 10.1002/mco2.218] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/22/2023] [Accepted: 01/30/2023] [Indexed: 03/29/2023] Open
Abstract
Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor-host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.
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Affiliation(s)
- Shiqi Nong
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Xiaoyue Han
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Yu Xiang
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Yuran Qian
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Yuhao Wei
- Department of Clinical MedicineWest China School of MedicineWest China HospitalSichuan UniversityChengduSichuanChina
| | - Tingyue Zhang
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Keyue Tian
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Kai Shen
- Department of OncologyFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jing Yang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xuelei Ma
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
- Department of Biotherapy and Cancer CenterState Key Laboratory of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
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Mukherjee S, Bhatti GK, Chhabra R, Reddy PH, Bhatti JS. Targeting mitochondria as a potential therapeutic strategy against chemoresistance in cancer. Biomed Pharmacother 2023; 160:114398. [PMID: 36773523 DOI: 10.1016/j.biopha.2023.114398] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/11/2023] Open
Abstract
The importance of mitochondria is not only limited to energy generation but also in several physical and chemical processes critical for cell survival. Mitochondria play an essential role in cellular apoptosis, calcium ion transport and cellular metabolism. Mutation in the nuclear and mitochondrial genes, altered oncogenes/tumor suppressor genes, and deregulated signalling for cell viability are major reasons for cancer progression and chemoresistance. The development of drug resistance in cancer patients is a major challenge in cancer treatment as the resistant cells are often more aggressive. The drug resistant cells of numerous cancer types exhibit the deregulation of mitochondrial function. The increased biogenesis of mitochondria and its dynamic alteration contribute to developing resistance. Further, a small subpopulation of cancer stem cells in the heterogeneous tumor is primarily responsible for chemoresistance and has an attribute of mitochondrial dysfunction. This review highlights the critical role of mitochondrial dysfunction in chemoresistance in cancer cells through the processes of apoptosis, autophagy/mitophagy, and cancer stemness. Mitochondria-targeted therapeutic strategies might help reduce cancer progression and chemoresistance induced by various cancer drugs.
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Affiliation(s)
- Soumi Mukherjee
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India.
| | - Ravindresh Chhabra
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, India.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience and Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Jasvinder Singh Bhatti
- Laboratory of Translational Medicine and Nanotherapeutics, Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
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The Role of Reprogrammed Glucose Metabolism in Cancer. Metabolites 2023; 13:metabo13030345. [PMID: 36984785 PMCID: PMC10051753 DOI: 10.3390/metabo13030345] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/19/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cancer cells reprogram their metabolism to meet biosynthetic needs and to adapt to various microenvironments. Accelerated glycolysis offers proliferative benefits for malignant cells by generating glycolytic products that move into branched pathways to synthesize proteins, fatty acids, nucleotides, and lipids. Notably, reprogrammed glucose metabolism and its associated events support the hallmark features of cancer such as sustained cell proliferation, hijacked apoptosis, invasion, metastasis, and angiogenesis. Overproduced enzymes involved in the committed steps of glycolysis (hexokinase, phosphofructokinase-1, and pyruvate kinase) are promising pharmacological targets for cancer therapeutics. In this review, we summarize the role of reprogrammed glucose metabolism in cancer cells and how it can be manipulated for anti-cancer strategies.
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35
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Guo D, Meng Y, Jiang X, Lu Z. Hexokinases in cancer and other pathologies. CELL INSIGHT 2023; 2:100077. [PMID: 37192912 PMCID: PMC10120283 DOI: 10.1016/j.cellin.2023.100077] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/28/2022] [Accepted: 01/02/2023] [Indexed: 05/18/2023]
Abstract
Glucose metabolism is indispensable for cell growth and survival. Hexokinases play pivotal roles in glucose metabolism through canonical functions of hexokinases as well as in immune response, cell stemness, autophagy, and other cellular activities through noncanonical functions. The aberrant regulation of hexokinases contributes to the development and progression of pathologies, including cancer and immune diseases.
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Affiliation(s)
- Dong Guo
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Ying Meng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoming Jiang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
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36
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Abstract
Histone lactylation, an indicator of lactate level and glycolysis, has intrinsic connections with cell metabolism that represents a novel epigenetic code affecting the fate of cells including carcinogenesis. Through delineating the relationship between histone lactylation and cancer hallmarks, we propose histone lactylation as a novel epigenetic code priming cells toward the malignant state, and advocate the importance of identifying novel therapeutic strategies or dual-targeting modalities against lactylation toward effective cancer control. This review underpins important yet less-studied area in histone lactylation, and sheds insights on its clinical impact as well as possible therapeutic tools targeting lactylation.
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37
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Chae HS, Hong ST. Overview of Cancer Metabolism and Signaling Transduction. Int J Mol Sci 2022; 24:12. [PMID: 36613455 PMCID: PMC9819818 DOI: 10.3390/ijms24010012] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
Despite the remarkable progress in cancer treatment up to now, we are still far from conquering the disease. The most substantial change after the malignant transformation of normal cells into cancer cells is the alteration in their metabolism. Cancer cells reprogram their metabolism to support the elevated energy demand as well as the acquisition and maintenance of their malignancy, even in nutrient-poor environments. The metabolic alterations, even under aerobic conditions, such as the upregulation of the glucose uptake and glycolysis (the Warburg effect), increase the ROS (reactive oxygen species) and glutamine dependence, which are the prominent features of cancer metabolism. Among these metabolic alterations, high glutamine dependency has attracted serious attention in the cancer research community. In addition, the oncogenic signaling pathways of the well-known important genetic mutations play important regulatory roles, either directly or indirectly, in the central carbon metabolism. The identification of the convergent metabolic phenotypes is crucial to the targeting of cancer cells. In this review, we investigate the relationship between cancer metabolism and the signal transduction pathways, and we highlight the recent developments in anti-cancer therapy that target metabolism.
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Affiliation(s)
- Hee-Suk Chae
- Department of Obstetrics and Gynecology, Research Institute of Clinical Medicine of Jeonbuk National University, Biomedical Research Institute of Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
| | - Seong-Tshool Hong
- Department of Biomedical Sciences, Jeonbuk National University Medical School, Jeonju 561-712, Jeonnbuk, Republic of Korea
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Liu R, Liu X. Virtual Screening and Biological Activity Evaluation of New Potent Inhibitors Targeting Hexokinase-II. Molecules 2022; 27:7555. [PMID: 36364382 PMCID: PMC9658052 DOI: 10.3390/molecules27217555] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 10/30/2022] [Accepted: 11/02/2022] [Indexed: 09/29/2023] Open
Abstract
Hexokinase-II (HK-II), the rate-limiting step enzyme in the glycolysis pathway, expresses high levels of cancer cells compared with normal cells. Due to its pivotal role in the different aspects of cancer physiology including cellular proliferation, metastasis, and apoptosis, HK-II provides a new therapeutic target for cancer therapy. The structure-based virtual screening targeting HK-II was used to hit identifications from small molecule databases, and the select compounds were further evaluated in biological assays. Forty-seven compounds with the lowest binding energies were identified as potential HK-II inhibitors. Among them, nine compounds displayed the highest cytotoxicity to three different cancer cells. Based on the mechanism study, compounds 4244-3659 and K611-0094 showed an obvious inhibitory effect on the HK-II enzyme. This study identified two potential inhibitors of HK-II and can be helpful for developing potential drugs targeting HK-II in tumor therapy.
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Affiliation(s)
- Ruijuan Liu
- College of Physical Education, Northwest Normal University, Lanzhou 730070, China
| | - Xuewei Liu
- Department of Pharmacy, Jiangsu Food and Pharmaceutical Science College, Huaian 223003, China
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Paul S, Ghosh S, Kumar S. Tumor glycolysis, an essential sweet tooth of tumor cells. Semin Cancer Biol 2022; 86:1216-1230. [PMID: 36330953 DOI: 10.1016/j.semcancer.2022.09.007] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 09/23/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022]
Abstract
Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.
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Affiliation(s)
- Sumana Paul
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, 400076 Mumbai, India
| | - Saikat Ghosh
- Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Sushil Kumar
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, 400076 Mumbai, India.
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Yadav K, Singh D, Singh MR, Pradhan M. Nano-constructs targeting the primary cellular energy source of cancer cells for modulating tumor progression. OPENNANO 2022. [DOI: 10.1016/j.onano.2022.100107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Microfluidic Technologies in Tumour Metabolism. Int J Pharm 2022; 629:122370. [DOI: 10.1016/j.ijpharm.2022.122370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 10/12/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
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Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies. Cancers (Basel) 2022; 14:cancers14194568. [PMID: 36230492 PMCID: PMC9559313 DOI: 10.3390/cancers14194568] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/14/2022] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
Simple Summary Reprogramming of glucose metabolism is a hallmark of cancer and can be targeted by therapeutic agents. Some metabolism regulators, such as ivosidenib and enasidenib, have been approved for cancer treatment. Currently, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Furthermore, some natural products have shown efficacy in killing tumor cells by regulating glucose metabolism, offering novel therapeutic opportunities in cancer. However, most of them have failed to be translated into clinical applications due to low selectivity, high toxicity, and side effects. Recent studies suggest that combining glucose metabolism modulators with chemotherapeutic drugs, immunotherapeutic drugs, and other conventional anticancer drugs may be a future direction for cancer treatment. Abstract Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy.
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Lai HT, Naumova N, Marchais A, Gaspar N, Geoerger B, Brenner C. Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma. Front Cell Dev Biol 2022; 10:948097. [PMID: 36072341 PMCID: PMC9441498 DOI: 10.3389/fcell.2022.948097] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine.
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Affiliation(s)
- Hong Toan Lai
- CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l’oncogénèse pour de nouvelles approches thérapeutiques, Université Paris-Saclay, Villejuif, France
| | - Nataliia Naumova
- CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l’oncogénèse pour de nouvelles approches thérapeutiques, Université Paris-Saclay, Villejuif, France
| | - Antonin Marchais
- INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Nathalie Gaspar
- INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Birgit Geoerger
- INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Catherine Brenner
- CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l’oncogénèse pour de nouvelles approches thérapeutiques, Université Paris-Saclay, Villejuif, France
- *Correspondence: Catherine Brenner,
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Shan W, Zhou Y, Yip Tam K. The development of small-molecule inhibitors targeting hexokinase 2. Drug Discov Today 2022; 27:2574-2585. [DOI: 10.1016/j.drudis.2022.05.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/12/2022] [Accepted: 05/18/2022] [Indexed: 02/04/2023]
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Ascenção K, Szabo C. Emerging roles of cystathionine β-synthase in various forms of cancer. Redox Biol 2022; 53:102331. [PMID: 35618601 PMCID: PMC9168780 DOI: 10.1016/j.redox.2022.102331] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 04/29/2022] [Accepted: 05/04/2022] [Indexed: 12/12/2022] Open
Abstract
The expression of the reverse transsulfuration enzyme cystathionine-β-synthase (CBS) is markedly increased in many forms of cancer, including colorectal, ovarian, lung, breast and kidney, while in other cancers (liver cancer and glioma) it becomes downregulated. According to the clinical database data in high-CBS-expressor cancers (e.g. colon or ovarian cancer), high CBS expression typically predicts lower survival, while in the low-CBS-expressor cancers (e.g. liver cancer), low CBS expression is associated with lower survival. In the high-CBS expressing tumor cells, CBS, and its product hydrogen sulfide (H2S) serves as a bioenergetic, proliferative, cytoprotective and stemness factor; it also supports angiogenesis and epithelial-to-mesenchymal transition in the cancer microenvironment. The current article reviews the various tumor-cell-supporting roles of the CBS/H2S axis in high-CBS expressor cancers and overviews the anticancer effects of CBS silencing and pharmacological CBS inhibition in various cancer models in vitro and in vivo; it also outlines potential approaches for biomarker identification, to support future targeted cancer therapies based on pharmacological CBS inhibition.
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Hexokinase 2 Inhibition and Biological Effects of BNBZ and Its Derivatives: The Influence of the Number and Arrangement of Hydroxyl Groups. Int J Mol Sci 2022; 23:ijms23052616. [PMID: 35269760 PMCID: PMC8910004 DOI: 10.3390/ijms23052616] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 12/10/2022] Open
Abstract
Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b–2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified.
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Fu L, Jin W, Zhang J, Zhu L, Lu J, Zhen Y, Zhang L, Ouyang L, Liu B, Yu H. Repurposing non-oncology small-molecule drugs to improve cancer therapy: Current situation and future directions. Acta Pharm Sin B 2022; 12:532-557. [PMID: 35256933 PMCID: PMC8897051 DOI: 10.1016/j.apsb.2021.09.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/05/2021] [Accepted: 08/27/2021] [Indexed: 12/25/2022] Open
Abstract
Drug repurposing or repositioning has been well-known to refer to the therapeutic applications of a drug for another indication other than it was originally approved for. Repurposing non-oncology small-molecule drugs has been increasingly becoming an attractive approach to improve cancer therapy, with potentially lower overall costs and shorter timelines. Several non-oncology drugs approved by FDA have been recently reported to treat different types of human cancers, with the aid of some new emerging technologies, such as omics sequencing and artificial intelligence to overcome the bottleneck of drug repurposing. Therefore, in this review, we focus on summarizing the therapeutic potential of non-oncology drugs, including cardiovascular drugs, microbiological drugs, small-molecule antibiotics, anti-viral drugs, anti-inflammatory drugs, anti-neurodegenerative drugs, antipsychotic drugs, antidepressants, and other drugs in human cancers. We also discuss their novel potential targets and relevant signaling pathways of these old non-oncology drugs in cancer therapies. Taken together, these inspiring findings will shed new light on repurposing more non-oncology small-molecule drugs with their intricate molecular mechanisms for future cancer drug discovery.
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Stevens N, Allred K. Antidiabetic Potential of Volatile Cinnamon Oil: A Review and Exploration of Mechanisms Using In Silico Molecular Docking Simulations. Molecules 2022; 27:853. [PMID: 35164117 PMCID: PMC8840343 DOI: 10.3390/molecules27030853] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/14/2022] [Accepted: 01/22/2022] [Indexed: 11/17/2022] Open
Abstract
Cinnamon has been used as a flavoring and medicinal agent for centuries. Much research has focused on cinnamon bark powder, which contains antioxidants, flavonoids, carotenoids, vitamins, minerals, fiber, and small amounts of essential oil. However, isolated and concentrated cinnamon essential oil may also have important medicinal qualities, particularly in antidiabetic therapy. Some of the most common essential oil constituents identified in the literature include cinnamaldehyde, eugenol, and beta-caryophyllene. Due to their high concentration in cinnamon essential oil, these constituents are hypothesized to have the most significant physiological activity. Here, we present a brief review of literature on cinnamon oil and its constituents as they relate to glucose metabolism and diabetic pathogenesis. We also present molecular docking simulations of these cinnamon essential oil constituents (cinnamaldehyde, eugenol, beta-caryophyllene) that suggest interaction with several key enzymes in glucometabolic pathways.
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Zhou Y, Guo Y, Tam KY. Targeting glucose metabolism to develop anticancer treatments and therapeutic patents. Expert Opin Ther Pat 2022; 32:441-453. [PMID: 35001793 DOI: 10.1080/13543776.2022.2027912] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION One of the most distinctive hallmarks of cancer cells is increased glucose consumption for aerobic glycolysis which is named the Warburg effect. In recent decades, extensive research has been carried out to exploit this famous phenomenon, trying to detect promising targetable vulnerabilities in altered metabolism to fight cancer. Targeting aberrant glucose metabolism can perturb cancer malignant proliferation and even induce programmed cell death. AREAS COVERED This review covered the recent patents which focused on targeting key glycolytic enzymes including hexokinase, pyruvate dehydrogenase kinases and lactate dehydrogenase for cancer treatment. EXPERT OPINION Compared with the conventional cancer treatment, specifically targeting the well-known Achilles heel Warburg effect has attracted considerable attention. Although there is still no single glycolytic agent for clinical cancer treatment, the combination of glycolytic inhibitor with conventional anticancer drug or the combined use of multiple glycolytic inhibitors are being investigated extensively in recent years, which could emerge as attractive anticancer strategies.
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Affiliation(s)
- Yan Zhou
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China
| | - Yizhen Guo
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China
| | - Kin Yip Tam
- Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China
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Sun Q, Wu J, Zhu G, Li T, Zhu X, Ni B, Xu B, Ma X, Li J. Lactate-related metabolic reprogramming and immune regulation in colorectal cancer. Front Endocrinol (Lausanne) 2022; 13:1089918. [PMID: 36778600 PMCID: PMC9909490 DOI: 10.3389/fendo.2022.1089918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/27/2022] [Indexed: 01/27/2023] Open
Abstract
Changes in cellular metabolism involving fuel sources are well-known mechanisms of cancer cell differentiation in the context of carcinogenesis. Metabolic reprogramming is regulated by oncogenic signaling and transcriptional networks and has been identified as an essential component of malignant transformation. Hypoxic and acidified tumor microenvironment contributes mainly to the production of glycolytic products known as lactate. Mounting evidence suggests that lactate in the tumor microenvironment of colorectal cancer(CRC) contributes to cancer therapeutic resistance and metastasis. The contents related to the regulatory effects of lactate on metabolism, immune response, and intercellular communication in the tumor microenvironment of CRC are also constantly updated. Here we summarize the latest studies about the pleiotropic effects of lactate in CRC and the clinical value of targeting lactate metabolism as treatment. Different effects of lactate on various immune cell types, microenvironment characteristics, and pathophysiological processes have also emerged. Potential specific therapeutic targeting of CRC lactate metabolism is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcomes by reducing chemoresistance.
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Affiliation(s)
- Qianhui Sun
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jingyuan Wu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Guanghui Zhu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Tingting Li
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xiaoyu Zhu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Baoyi Ni
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bowen Xu
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Graduate College, Beijing University of Traditional Chinese Medicine, Beijing, China
| | - Xinyi Ma
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jie Li
- Oncology Department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: Jie Li,
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