|
1
|
Du C, Hu Y, Yang X, Zhang Z, Gu J, Zhang T, Wang R, Zhang S, Tan L, Yu G. SUMO-Specific Peptidase 5 Promotes Oesophageal Squamous Cell Carcinoma Growth through the NF-κB- SLC1A3 Axis. FRONT BIOSCI-LANDMRK 2025; 30:27047. [PMID: 39862098 DOI: 10.31083/fbl27047] [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: 10/20/2024] [Revised: 11/28/2024] [Accepted: 12/05/2024] [Indexed: 01/30/2025]
Abstract
BACKGROUND This study investigates the role of small ubiquitin-like modifier (SUMO)-specific peptidase 5 (SENP5), a key regulator of SUMOylation, in esophageal squamous cell carcinoma (ESCC), a lethal disease, and its underlying molecular mechanisms. METHODS Differentially expressed genes between ESCC mouse oesophageal cancer tissues and normal tissues were analysed via RNA-seq; among them, SENP5 expression was upregulated, and this gene was selected for further analysis. Immunohistochemistry and western blotting were then used to validate the increased protein level of SENP5 in both mouse and human ESCC samples. The Kaplan‒Meier method and multivariate analysis were used to analyse the relationship between SENP5 expression and ESCC prognosis. Stable SENP5-knockdown (KD) cell lines and conditional knockout (cKO) mice were established to verify the biological function of SENP5. Further RNA-seq comparisons between short hairpin SENP5 (shSENP5)- and short hairpin negative control (shNC)-transfected ESCC cell lines were conducted, and the nuclear factor kappa B (NF-κB)-SLC1A3 axis was identified through bioinformatics analysis. The correlation of SENP5 with signalling pathway components was validated via real-time quantitative PCR (qPCR), western blotting (WB), and immunoprecipitation. RESULTS Our study revealed that SENP5 was upregulated in human and mouse ESCC samples, and clinical data analysis revealed a correlation between high SENP5 expression and poor patient prognosis. SENP5 knockdown inhibited tumorigenesis and growth in vivo and suppressed the proliferation, migration, and invasion of ESCC cell lines in vitro. Our study also revealed that SENP5 knockdown enhanced the SUMO1-mediated SUMOylation of NF-kappa-B inhibitor alpha (IκBα), thereby inhibiting the activation of the NF-κB-SLC1A3 axis, which subsequently suppresses ESCC cell energy metabolism and impedes ESCC progression. CONCLUSIONS Suppression of SENP5 slows the development of ESCC by inhibiting the NF-κB‒SLC1A3 axis through SUMO1-mediated SUMOylation of IκBα. Our research suggests that SENP5 could serve as a prognostic indicator and a target for therapeutic intervention for ESCC patients.
Collapse
Affiliation(s)
- Chaoxiang Du
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
- Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, 361006 Xiamen, Fujian, China
| | - Yunfan Hu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
| | - Xinyu Yang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
| | - Zhe Zhang
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Nantong University, 214400 Jiangyin, Jiangsu, China
| | - Jianmin Gu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
- Department of Vascular Surgery, General Surgery Clinical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China
| | - Tao Zhang
- Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, 361006 Xiamen, Fujian, China
| | - Renfeng Wang
- Department of Thoracic Surgery, Zhongshan Hospital (Xiamen), Fudan University, 361006 Xiamen, Fujian, China
| | - Shaoyuan Zhang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
| | - Guiping Yu
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Nantong University, 214400 Jiangyin, Jiangsu, China
| |
Collapse
|
|
2
|
Li X, Han H, Yang K, Li S, Ma L, Yang Z, Zhao YX. Crosstalk between thyroid CSCs and immune cells: basic principles and clinical implications. Front Immunol 2024; 15:1476427. [PMID: 39776907 PMCID: PMC11703838 DOI: 10.3389/fimmu.2024.1476427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/04/2024] [Indexed: 01/11/2025] Open
Abstract
Thyroid cancer has become the most common endocrine malignancy. Although the majority of differentiated thyroid cancers have a favorable prognosis, advanced thyroid cancers, iodine-refractory thyroid cancers, and highly malignant undifferentiated carcinomas still face a serious challenge of poor prognosis and even death. Cancer stem cells are recognized as one of the central drivers of tumor evolution, recurrence and treatment resistance. A fresh viewpoint on the oncological aspects of thyroid cancer, including proliferation, invasion, recurrence, metastasis, and therapeutic resistance, has been made possible by the recent thorough understanding of the defining and developing features as well as the plasticity of thyroid cancer stem cells (TCSCs). The above characteristics of TCSCs are complicated and regulated by cell-intrinsic mechanisms (including activation of key stem signaling pathways, somatic cell dedifferentiation, etc.) and cell-extrinsic mechanisms. The complex communication between TCSCs and the infiltrating immune cell populations in the tumor microenvironment (TME) is a paradigm for cell-extrinsic regulators. This review introduces the current advances in the studies of TCSCs, including the origin of TCSCs, the intrinsic signaling pathways regulating the stemness of TCSCs, and emerging biomarkers; We further highlight the underlying principles of bidirectional crosstalk between TCSCs and immune cell populations driving thyroid cancer progression, recurrence, or metastasis, including the specific mechanisms by which immune cells maintain the stemness and other properties of TCSCs and how TCSCs reshape the immune microenvironmental landscape to create an immune evasive and pro-tumorigenic ecological niche. Finally, we outline promising strategies and challenges for targeting key programs in the TCSCs-immune cell crosstalk process to treat thyroid cancer.
Collapse
Affiliation(s)
- Xiaoxiao Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Hengtong Han
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Kaili Yang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Shouhua Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Libin Ma
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ze Yang
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yong-xun Zhao
- The Seventh Department of General Surgery, Department of Thyroid Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| |
Collapse
|
|
3
|
Hlozkova K, Vasylkivska M, Boufersaoui A, Marzullo B, Kolarik M, Alquezar-Artieda N, Shaikh M, Alaei NF, Zaliova M, Zwyrtkova M, Bakardijeva-Mihaylova V, Alberich-Jorda M, Trka J, Tennant DA, Starkova J. Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase. Cancer Lett 2024; 605:217242. [PMID: 39270769 DOI: 10.1016/j.canlet.2024.217242] [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: 03/13/2024] [Revised: 09/02/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024]
Abstract
Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.
Collapse
Affiliation(s)
- Katerina Hlozkova
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic.
| | - Maryna Vasylkivska
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic
| | - Adam Boufersaoui
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Bryan Marzullo
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Matus Kolarik
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Natividad Alquezar-Artieda
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic
| | - Mehak Shaikh
- Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Nadia Fatemeh Alaei
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Marketa Zaliova
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic
| | - Martina Zwyrtkova
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic
| | - Violeta Bakardijeva-Mihaylova
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic
| | - Meritxell Alberich-Jorda
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; Laboratory of Hemato-Oncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jan Trka
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic
| | - Daniel A Tennant
- Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Julia Starkova
- Childhood Leukaemia Investigation Prague, Prague, Czech Republic; Second Faculty of Medicine, Department of Pediatric Hematology and Oncology, Charles University, Prague, Czech Republic; University Hospital Motol, Prague, Czech Republic.
| |
Collapse
|
|
4
|
Zhi R, Fan F. SLC1A3 is a novel prognostic biomarker associated with immunity and EMT in hepatocellular carcinoma. Discov Oncol 2024; 15:676. [PMID: 39560677 DOI: 10.1007/s12672-024-01561-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 11/08/2024] [Indexed: 11/20/2024] Open
Abstract
PURPOSE Solute carrier family 1 member 3(SLC1A3), a member of the glutamate transporter family, is implicated in the progression of gastric carcinoma and the renewal of thyroid carcinoma stem cells. The purpose of this work is to use experimental validation and bioinformatics analysis to look at the possible involvement of SLC1A3 in hepatocellular carcinoma (HCC). MATERIALS AND METHODS We examined the levels of SLC1A3 within HCC and its implications on immunological and epithelial-mesenchymal transition (EMT) features using the TCGA, ImmPort, and Molecular Signatures databases. The relationship between drug sensitivity and SLC1A3 expression was investigated using the GDSC database. Real-time quantitative polymerase chain reaction (qRT-PCR), Western blotting (WB), and cellular function assays were performed to assess SLC1A3 expression and its carcinogenic effects in HCC. RESULTS According to our research, SLC1A3 overexpression in HCC is associated with a poor prognosis. Elevated levels of SLC1A3 promote HCC cell motility and invasion and can affect the prognosis of HCC by modifying immune responses and epithelial-mesenchymal transition. SLC1A3 has emerged as a novel prognostic marker in HCC and is associated with resistance to certain antitumor drugs. CONCLUSION SLC1A3 functions as a cancer-promoting factor contributing to poor HCC prognosis by affecting immune cell infiltration and regulating the EMT process. Elevated SLC1A3 expression may also serve as a predictor of treatment response to specific antitumor drugs.
Collapse
Affiliation(s)
- Renhou Zhi
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Fan Fan
- Department of Gastroenterology, Shanxi Hospital Affiliated to Cancer Hospital, Shanxi Province Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital, Shanxi Medical University, Taiyuan, China.
| |
Collapse
|
|
5
|
Hushmandi K, Einollahi B, Saadat SH, Lee EHC, Farani MR, Okina E, Huh YS, Nabavi N, Salimimoghadam S, Kumar AP. Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy. Mol Metab 2024; 84:101952. [PMID: 38705513 PMCID: PMC11112377 DOI: 10.1016/j.molmet.2024.101952] [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: 03/21/2024] [Revised: 04/24/2024] [Accepted: 04/27/2024] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND Solute carrier (SLC) transporters, a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment (TME). Amino acids are fundamental building blocks of cells and play essential roles in protein synthesis, nutrient sensing, and oncogenic signaling pathways. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies. SCOPE OF REVIEW In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions. MAJOR CONCLUSIONS Amino acids transportation by SLCs plays a critical role in tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although several studies evaluated the function of SLC7A11 and SLC1A5, the role of some SLC proteins in cancer is not studied well. To exert their functions, SLCs mediate metabolic rewiring, regulate the maintenance of redox balance, affect main oncogenic pathways, regulate amino acids bioavailability within the TME, and alter the sensitivity of cancer cells to therapeutics. However, different therapeutic methods that prevent the function of SLCs were able to inhibit tumor progression. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids and their transporters within the SLC superfamily.
Collapse
Affiliation(s)
- Kiavash Hushmandi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Behzad Einollahi
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Hassan Saadat
- Nephrology and Urology Research Center, Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - E Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Marzieh Ramezani Farani
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
| | - Elena Okina
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yun Suk Huh
- NanoBio High-Tech Materials Research Center, Department of Biological Sciences and Bioengineering, Inha University, Incheon 22212, Republic of Korea
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6, Vancouver, BC, Canada
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
6
|
Peng X, Zhu P, Zhang Q, Li J. The prognostic value of cancer stem cell markers in thyroid cancer: a systematic review. Arch Med Sci 2024; 20:686-690. [PMID: 38757036 PMCID: PMC11094817 DOI: 10.5114/aoms/185169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 02/22/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction Thyroid cancer stem cells (TCSCs) play a crucial role in the pathogenesis, metastasis, and therapeutic response of thyroid cancer, making them promising biomarkers and potential targets for clinical intervention. This systematic review aims to qualitatively assess the impact of commonly used TCSC markers on the prognosis of thyroid cancer using qualitative methods. Methods In total, the analysis encompassed five articles. Results Six TCSC markers were involved, among which CD133, CD44, CD24, CD15 and ALDH1 were associated with the prognosis of thyroid cancer. Conclusions However, the utility of these TCSC markers in clinical practice for predicting the prognosis of thyroid cancer requires further research to provide additional evidence supporting their effectiveness.
Collapse
Affiliation(s)
- Xingqiao Peng
- Department of Oncology, Army Medical Center of PLA, Chongqing, China
| | - Peiye Zhu
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Qiang Zhang
- Department of Oncology, Army Medical Center of PLA, Chongqing, China
- College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Jin Li
- Department of Oncology, Army Medical Center of PLA, Chongqing, China
| |
Collapse
|
|
7
|
Gisina A, Kim Y, Yarygin K, Lupatov A. Can CD133 Be Regarded as a Prognostic Biomarker in Oncology: Pros and Cons. Int J Mol Sci 2023; 24:17398. [PMID: 38139228 PMCID: PMC10744290 DOI: 10.3390/ijms242417398] [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: 10/30/2023] [Revised: 12/07/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
The CD133 cell membrane glycoprotein, also termed prominin-1, is expressed on some of the tumor cells of both solid and blood malignancies. The CD133-positive tumor cells were shown to exhibit higher proliferative activity, greater chemo- and radioresistance, and enhanced tumorigenicity compared to their CD133-negative counterparts. For this reason, CD133 is regarded as a potential prognostic biomarker in oncology. The CD133-positive cells are related to the cancer stem cell subpopulation in many types of cancer. Recent studies demonstrated the involvement of CD133 in the regulation of proliferation, autophagy, and apoptosis in cancer cells. There is also evidence of its participation in the epithelial-mesenchymal transition associated with tumor progression. For a number of malignant tumor types, high CD133 expression is associated with poor prognosis, and the prognostic significance of CD133 has been confirmed in a number of meta-analyses. However, some published papers suggest that CD133 has no prognostic significance or even demonstrate a certain correlation between high CD133 levels and a positive prognosis. This review summarizes and discusses the existing evidence for and against the prognostic significance of CD133 in cancer. We also consider possible reasons for conflicting findings from the studies of the clinical significance of CD133.
Collapse
Affiliation(s)
- Alisa Gisina
- Laboratory of Cell Biology, V. N. Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia
| | | | | | | |
Collapse
|
|
8
|
Glutamine Metabolism in Cancer Stem Cells: A Complex Liaison in the Tumor Microenvironment. Int J Mol Sci 2023; 24:ijms24032337. [PMID: 36768660 PMCID: PMC9916789 DOI: 10.3390/ijms24032337] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
In this review we focus on the role of glutamine in control of cancer stem cell (CSC) fate. We first provide an overview of glutamine metabolism, and then summarize relevant studies investigating how glutamine metabolism modulates the CSC compartment, concentrating on solid tumors. We schematically describe how glutamine in CSC contributes to several metabolic pathways, such as redox metabolic pathways, ATP production, non-essential aminoacids and nucleotides biosynthesis, and ammonia production. Furthermore, we show that glutamine metabolism is a key regulator of epigenetic modifications in CSC. Finally, we briefly discuss how cancer-associated fibroblasts, adipocytes, and senescent cells in the tumor microenvironment may indirectly influence CSC fate by modulating glutamine availability. We aim to highlight the complexity of glutamine's role in CSC, which supports our knowledge about metabolic heterogeneity within the CSC population.
Collapse
|
|
9
|
Zhang Q, Li W. Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy. World J Stem Cells 2022; 14:267-286. [PMID: 35662861 PMCID: PMC9136564 DOI: 10.4252/wjsc.v14.i4.267] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/19/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.
Collapse
Affiliation(s)
- Qi Zhang
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wei Li
- Cancer Center, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| |
Collapse
|
|
10
|
Zhong X, Yao L, Xu L, Ma Q, Huang G, Yang M, Gao C, Cheng J, Zhou X, Li Q, Guo X. Comprehensive Analysis of Potential Correlation Between Solute Carrier 1A (SLC1A) Family and Lung Adenocarcinoma. Int J Gen Med 2022; 15:2101-2117. [PMID: 35241927 PMCID: PMC8886152 DOI: 10.2147/ijgm.s350986] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Background Lung adenocarcinoma (LUAD) is the most common dangerous malignant tumor and the leading cause of global cancer incidence and mortality. The Solute Carrier 1A (SLC1A) family play a significant part in cellular biological process, inflammation, and immunity. Specific functions of the SLC1A family in lung cancer are still not systematically described. Objective This study aimed to explore the best biological understanding of SLC1A family in lung cancer. Methods To study the expression and role of the SLC1A family in lung cancer, researchers used a variety of bioinformatics databases and tools. Results Aberrant expression of SLC1A family genes were demonstrated and analyzed the association with gender, tumor grade, cancer stages, and nodal metastasis status. The ectopic expression of SLC1A family genes has prognostic value for LUAD patients. Immune infiltration revealed a significant correlation between SLC1A family genes expression in LUAD. SLC1A family genes were involved in manifold biological processes and have different levels of DNA methylation and genetic alteration. Conclusions These findings suggested that members of the SLC1A family could be a potential target for the development of LUAD therapeutics as well as a reliable indicator of LUAD prognostic value.
Collapse
Affiliation(s)
- Xiaowu Zhong
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Lihua Yao
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Lei Xu
- Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Qiang Ma
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Guangcheng Huang
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Miyuan Yang
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Chuanli Gao
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Jibing Cheng
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Xi Zhou
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Qinrong Li
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
| | - Xiaolan Guo
- Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Department of Laboratory Medicine, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, People’s Republic of China
- Correspondence: Xiaolan Guo, Department of Clinical Laboratory, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, People’s Republic of China, Tel +86-817-2282059, Fax +86-817-2282059, Email
| |
Collapse
|
|
11
|
Parvanova I, Borziak K, Guarino J, Finkelstein J. A Platform for Integrating and Sharing Cancer Stem Cell Data. ANNUAL INTERNATIONAL CONFERENCE OF THE IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. IEEE ENGINEERING IN MEDICINE AND BIOLOGY SOCIETY. ANNUAL INTERNATIONAL CONFERENCE 2021; 2021:2320-2325. [PMID: 34891750 DOI: 10.1109/embc46164.2021.9630083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Advancements in cancer research and treatment have highlighted the need for standardization and sharing of cancer stem cell (CSC) data to facilitate research transparency and to promote collaboration within the scientific community. Although previous applications have attempted to gather and disseminate these data, currently no platform organizes the heterogeneous CSC information into a harmonized project-based framework. The aim of our platform, ReMeDy, is to provide an intelligent informatics solution integrating diverse CSC characteristics, outcomes information, and omics data across clinical, preclinical and in vitro studies. These heterogeneous data streams are organized within a multi-modular framework, subjected to a stringent validation by using standardized ontologies, and stored in a searchable format. To test usefulness of our approach for capturing diverse data related to CSCs, we integrated data from 52 publicly-available CSC projects. We validated the robustness of the platform, by efficiently organizing diverse data elements, and demonstrated its potential for promoting future knowledge discovery driven by aggregation of published data. Next steps include expanding number of uploaded CSC projects and developing additional data visualization tools. The platform is accessible through https://remedy.mssm.edu/.
Collapse
|
|
12
|
Wang Y, Hu Z, Ma W, Niu Y, Su J, Zhang L, Zhao P. Signal transducer and activator of transcription 3 inhibition alleviates resistance to BRAF inhibition in anaplastic thyroid cancer. Invest New Drugs 2021; 39:764-774. [PMID: 33245464 DOI: 10.1007/s10637-020-01024-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/20/2020] [Indexed: 12/15/2022]
Abstract
Anaplastic thyroid cancer (ATC) is a rare type of thyroid cancer (TC) with no effective therapeutic strategy. Although surgery, chemotherapy and radiation are all available for ATC treatment, the median survival for ATC patients is less than 6 months. In this study, we aimed to study on resistant mechanisms to B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor and identify effective combinational therapy for ATC patients. TC cells were treated with Vemurafenib and cell apoptosis and viability were analyzed by flow cytometry and MTT assay. Monolayer and sphere cells were isolated from ATC cells to detect the mRNA level of stem cell markers and differentiation markers by RT-PCR. Phosphor-STAT3 level in sphere and monolayer cells was tested by Western blotting. The xenotransplantation animal model has established to analyze the anti-tumor effect of Vemurafenib and Stattic combinational therapy. Undifferentiated TC cells were resistant to Vemurafenib treatment. Sphere cells isolated from ATC showed no significant change in cell viability and apoptosis upon Vemurafenib treatment, and expressed a high level of stem cell marker and phosphor-STAT3. STAT3 inhibition enhanced the tumorigenic capacity and increased Vemurafenib sensitivity in ATC cell lines. Stattic significantly enhanced anti-tumor effect of Vemurafenib in mouse model. Our findings demonstrate that the combinational therapy of Vemurafenib and Stattic is an effective therapeutic treatment for ATC patients.
Collapse
Affiliation(s)
- Ying Wang
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Zhigang Hu
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Weiyuan Ma
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China
| | - Yong Niu
- Quyang People's Hospital, Taihang Road, Quyang County, Baoding, 071000, Hebei, China
| | - Jingwei Su
- Quyang People's Hospital, Taihang Road, Quyang County, Baoding, 071000, Hebei, China
| | - Lingxiang Zhang
- Xingtai Ninth Hospital, No.163 Jiankang East Road, Julu County, Xingtai, 054000, Hebei, China
| | - Pengxin Zhao
- The Second Hospital of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang, 050000, Hebei, China.
| |
Collapse
|
|
13
|
Xu L, Chen J, Jia L, Chen X, Awaleh Moumin F, Cai J. SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. J Cell Mol Med 2020; 24:14392-14404. [PMID: 33145952 PMCID: PMC7753768 DOI: 10.1111/jcmm.16060] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 09/27/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is a major cause of mortality worldwide. The glutamate/aspartate transporter SLC1A3 has been implicated in tumour metabolism and progression, but the roles of SLC1A3 in gastric cancer remain unclear. We used bioinformatics approaches to analyse the expression of SLC1A3 and its role in gastric cancer. The expression levels of SLC1A3 were examined using RT-qPCR and Western bolting. SLC1A3 overexpressing and knock-down cell lines were constructed, and the cell viability was evaluated. Glucose consumption, lactate excretion and ATP levels were determined. The roles of SLC1A3 in tumour growth were evaluated using a xenograft tumour growth model. SLC1A3 was found to be overexpressed in gastric cancer, and this overexpression was associated with poor prognosis. In vitro and in vivo assays showed that SLC1A3 affected glucose metabolism and promoted gastric cancer growth. GSEA analysis suggested that SLC1A3 was positively associated with the up-regulation of the PI3K/AKT pathway. SLC1A3 overexpression activated the PI3K/AKT pathway and up-regulated GLUT1, HK II and LDHA expression. The PI3K/AKT inhibitor LY294002 prevented SLC1A3-induced glucose metabolism and cell proliferation. Our findings indicate that SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. SLC1A3 is therefore a potential therapeutic target in gastric cancer.
Collapse
Affiliation(s)
- Liyi Xu
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jiamin Chen
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Litao Jia
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Xiao Chen
- Emergency Departmentthe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Faycal Awaleh Moumin
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jianting Cai
- Department of Gastroenterologythe Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| |
Collapse
|
|
14
|
Karas Zella MA, Sebastião APM, Collaço LM, Ogata DC, Cecchetti G, Bartolomei IJP, Waaga-Gasser AM, Ribas CAPM. Prognostic significance of CD133 and ABCB5 expression in papillary thyroid carcinoma. Eur J Histochem 2020; 64. [PMID: 33207860 PMCID: PMC7674992 DOI: 10.4081/ejh.2020.3143] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 11/03/2020] [Indexed: 01/06/2023] Open
Abstract
Expression of CD133 and ABCB5 is associated with tumor aggressiveness, but evidence in papillary thyroid cancer (PTC) is lacking. We correlated CD133 and ABCB5 expression with pathological characteristics and factors of worse prognosis in PTC. Samples of 119 PTCs and 40 controls (goiters) were distributed in 8 tissue microarray blocks and evaluated with immunohistochemistry using anti-CD133 and anti-ABCB5 antibodies. The expression of each marker alone and combined was analyzed against pathological characteristics and factors of worse prognosis in PTC. Expression of CD133 alone (19 tumors, 16.0%) was more frequent in patients with versus without lymph node metastases (P=0.024). Expression of ABCB5 alone (n=95, 83.3%) was associated with larger tumor size (P=0.045). CD133-ABCB5 coexpression was not associated with pathological characteristics or factors of worse prognosis in PTC.
Collapse
Affiliation(s)
| | | | | | - Daniel Cury Ogata
- Department of Pathology, Universidade do Vale do Itajai, Santa Catarina.
| | | | | | | | | |
Collapse
|
|
15
|
Single-cell RNA sequencing reveals the regenerative potential of thyroid follicular epithelial cells in metastatic thyroid carcinoma. Biochem Biophys Res Commun 2020; 531:552-558. [PMID: 32811644 DOI: 10.1016/j.bbrc.2020.06.050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 06/10/2020] [Indexed: 02/07/2023]
Abstract
Thyroid stimulating hormone deficiency is the cornerstone of treatment for metastatic thyroid cancer. Due to the loss of follicular epithelial cells in thyroid cancer, the thyroid gland degenerates to 85% of its original size. When thyroid stimulating hormone is restored, follicular epithelial cells in thyroid cancer regenerate, which is postulated to be related to stem-like cells. By single cell RNA seq, we found a group of rare thyroid follicular epithelial cells in mouse metastatic thyroid cancer, which expressed stem-like genes (CD44V6+ and CD133+) and a large number of differentiated cells (CD44V6+ and CD24+). In mouse and in organoids, the two subsets contribute equally to metastatic thyroid cancer regeneration. The analysis of human metastatic thyroid cancer revealed that the differentiated thyroid follicular epithelial cell subpopulation was similar to that of the stem like epithelial cell subpopulation, and the regeneration potential was also enhanced after thyroid stimulating hormone ablation. Accordingly, we propose that the regeneration of metastatic thyroid cancer is driven by almost all persistent thyroid follicular epithelial cells, not only by few stem-like cells.
Collapse
|
|
16
|
Zhao H, Chen S, Fu Q. Exosomes from CD133 + cells carrying circ-ABCC1 mediate cell stemness and metastasis in colorectal cancer. J Cell Biochem 2020; 121:3286-3297. [PMID: 31960989 DOI: 10.1002/jcb.29600] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 12/11/2019] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC), a fatal tumor, has been diagnosed as one of the most prevalent types of cancers globally, inducing multiple cancer-linked deaths. Mounting evidence has revealed that circular RNA (circRNA) elicits a regulatory impact on the initiation and development of cancers. Emerged as a new circRNA, hsa_circ_0000677 (circ-ABCC1) has not been studied in cancer progression. This study is the first attempt to explore the regulatory role of circ-ABCC1 in CRC. In this study, data from sphere-forming, transwell, and Western blot analyses revealed that cell stemness, sphere formation, and metastasis were notably enhanced in CD133+ cells isolated from CRC cells. In addition, exosomes from CD133+ cells could promote cell stemness, sphere formation, and metastasis. Moreover, circ-ABCC1 was verified to be characterized with a loop structure through quantitative reverse-transcription polymerase chain reaction analysis. Functional assays testified that the upregulation of circ-ABCC1 contributed to cell stemness, sphere formation, and metastasis in CD133- /Caco2 or CD133- /HCT15 cells. Furthermore, the interaction between circ-ABCC1 and β-catenin was analyzed via RNA immunoprecipitation and RNA pull-down and finally, circ-ABCC1 was confirmed to facilitate CRC progression by activating the Wnt/β-catenin pathway. To sum up, exosomes from CD133+ cells carrying circ-ABCC1 can mediate cell stemness and metastasis in CRC, unveiling that circ-ABCC1 serves as a novel candidate target for CRC treatment.
Collapse
Affiliation(s)
- Hong Zhao
- Department of General Surgery, Hebi Coal Industry (Group) Co, Ltd, General Hospital, Hebi City, Henan Province, China
| | - Shixia Chen
- Department of Joint Trauma Orthopaedics, Weifang Yidu Central Hospital, Weifang, China
| | - Qiang Fu
- Department of Minimally Invasive Gastrointestinal Surgery, Henan Tumor Hospital, Zhengzhou City, Henan Province, China
| |
Collapse
|
|
17
|
Wang Z, Liu W, Wang C, Li Y, Ai Z. Acetylcholine promotes the self-renewal and immune escape of CD133+ thyroid cancer cells through activation of CD133-Akt pathway. Cancer Lett 2019; 471:116-124. [PMID: 31830559 DOI: 10.1016/j.canlet.2019.12.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 02/08/2023]
Abstract
Nerves infiltrate the tumor microenvironment and stimulate the growth of cancer cells through the secretion of neurotransmitters. However, the contributions of nerves to the self-renewal capacity of cancer stem cells (CSCs) remain largely unknown. In this study, we found that CD133+ cancer cells were responsible for the initiation of thyroid cancer. Neurons were juxtaposed with CD133+ cells in thyroid cancer tissues. Acetylcholine, one of the most abundant neurotransmitters, promoted CD133 Y828 phosphorylation, and subsequently increased the interaction between CD133 and PI3K regulatory subunit p85, resulting in the activation of the PI3K-Akt pathway. Acetylcholine increased the self-renewal ability of CD133+ thyroid cancer cells through activation of CD133-Akt pathway. Furthermore, acetylcholine promoted the expression of the immune regulator PD-L1 through the activation of the CD133-Akt pathway, resulting in the resistance of CD133+ thyroid cancer cells to CD8+ T cells. However, acetylcholine receptor antagonist 4-DAMP blocked the positive effects of acetylcholine on the self-renewal and immune escape of CD133+ thyroid cancer cells. Taken together, these data suggest that acetylcholine increases the self-renewal and immune escape abilities of CD133+ thyroid cancer cells through the activation of the CD133-Akt pathway.
Collapse
Affiliation(s)
- Zhenglin Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wei Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Cong Wang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yinan Li
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Zhilong Ai
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| |
Collapse
|