D-Mannose Upregulates Testin via the NF-κB Pathway to Inhibit Breast Cancer Proliferation
Xue Cao
The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorXinlan Liu
Department of Medical Oncology, Ningxia Hui Autonomous Region Hospital, Yinchuan, Ningxia, China
Search for more papers by this authorPing Chen
Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorTingting Wei
Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorQingxia Zhou
Oncology Department, Wuzhong People's Hospital, Wuzhong, Ningxia, China
Search for more papers by this authorGuoxin Zhang
The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorTong She
Oncology Department, Hospital of Zhongwei, Zhongwei, Ningxia, China
Search for more papers by this authorCorresponding Author
Zhisheng Wang
School of Inspection, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
Correspondence: Zhisheng Wang ([email protected])
Yaobang Liu ([email protected])
Search for more papers by this authorCorresponding Author
Yaobang Liu
Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
Correspondence: Zhisheng Wang ([email protected])
Yaobang Liu ([email protected])
Search for more papers by this authorXue Cao
The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorXinlan Liu
Department of Medical Oncology, Ningxia Hui Autonomous Region Hospital, Yinchuan, Ningxia, China
Search for more papers by this authorPing Chen
Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorTingting Wei
Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorQingxia Zhou
Oncology Department, Wuzhong People's Hospital, Wuzhong, Ningxia, China
Search for more papers by this authorGuoxin Zhang
The First School of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
Search for more papers by this authorTong She
Oncology Department, Hospital of Zhongwei, Zhongwei, Ningxia, China
Search for more papers by this authorCorresponding Author
Zhisheng Wang
School of Inspection, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
Correspondence: Zhisheng Wang ([email protected])
Yaobang Liu ([email protected])
Search for more papers by this authorCorresponding Author
Yaobang Liu
Department of Surgical Oncology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China
Correspondence: Zhisheng Wang ([email protected])
Yaobang Liu ([email protected])
Search for more papers by this authorXue Cao and Xinlan Liu contributed equally to this work.
ABSTRACT
d-Mannose is a naturally occurring monosaccharide known to enhance the effects of chemotherapy, immunotherapy, and radiotherapy in cancer patients. This study aimed to investigate the growth-regulating mechanism of d-mannose on breast cancer (BC) cells. d-mannose was treated on MDA-MB-231 and MCF-7 BC cells. Cell counting kit-8 (CCK-8), wound healing test, transwell invasion, and flow cytometry assays were used to assess the viability, invasion, migration, and apoptosis of d-mannose treated BC cells. Testin (TES) expressions in d-mannose treated BC cells were evaluated using western blot analysis, qRT-PCR, and immunofluorescence assays. The potential regulatory relationship between d-mannose and TES in BC cells were explored by analyzing TES gene expression profile in BC cells using the University of California Santa Cruz (UCSC) Xena browser database. Immunohistochemical analysis of TES protein was performed in BC tissue samples obtained from patients. It was found that d-mannose significantly inhibited the growth of MDA-MB-231 and MCF-7 cells in a concentration and time-dependent manner by activating the NF-κB signaling pathway and upregulating TES expression. TES knockdown downregulated the NF-κB1, NF-κB2, and p65 protein expressions. Therefore, this study highlights that d-mannose have the potential to promote anticancer effects upon further trials using in vivo models and clinical studies.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data underlying this article are available and will be provided upon reasonable request from the corresponding author.
References
- 1H. Sung, J. Ferlay, R. L. Siegel, et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71, no. 3 (2021): 209–249.
- 2S. Wang, D. Yang, J. Mo, M. Chen, and R. Zhang, “The Role of Pyroptosis-Related Genes in Breast Cancer Progression,” Tumor Discovery 3, no. 3 (2024): 3469.
10.36922/td.3469 Google Scholar
- 3K. D. Voduc, M. C. U. Cheang, S. Tyldesley, K. Gelmon, T. O. Nielsen, and H. Kennecke, “Breast Cancer Subtypes and the Risk of Local and Regional Relapse,” Journal of Clinical Oncology 28, no. 10 (2010): 1684–1691.
- 4N. Harbeck, F. Penault-Llorca, J. Cortes, et al., “Breast Cancer,” Nature Reviews Disease Primers 5, no. 1 (2019): 66.
- 5A. B. Hanker, D. R. Sudhan, and C. L. Arteaga, “Overcoming Endocrine Resistance in Breast Cancer,” Cancer Cell 37, no. 4 (2020): 496–513.
- 6X. Fu, R. Pereira, C. De Angelis, et al., “FOXA1 Upregulation Promotes Enhancer and Transcriptional Reprogramming in Endocrine-Resistant Breast Cancer,” Proceedings of the National Academy of Sciences of the United States of America 116, no. 52 (2019): 26823–26834.
- 7S. T. Parambil, G. R. Antony, A. B. Littleflower, et al., “Verteporfin Induces YAP-Dependent Cell Cycle Arrest and Caspase-Mediated Cellular Apoptosis in Triple-Negative Breast Cancer Cells [J],” Gene & Protein in Disease 2, no. 2 (2023): 0658.
- 8M. Sarti, C. Sevignani, G. A. Calin, et al., “Adenoviral Transduction of Testin Gene into Breast and Uterine Cancer Cell Lines Promotes Apoptosis and Tumor Reductionin Vivo,” Clinical Cancer Research 11, no. 2 pt. 1 (2005): 806–813.
- 9A. Popiel, C. Kobierzycki, and P. Dzięgiel, “The Role of Testin in Human Cancers,” Pathology & Oncology Research 25, no. 4 (2019): 1279–1284.
- 10R. Dong, H. Pu, Y. Wang, J. Yu, K. Lian, and C. Mao, “Testin Was Commonly Hypermethylated and Involved in the Epithelial-Mesenchymal Transition of Endometrial Cancer,” APMIS 123, no. 5 (2015): 394–400.
- 11R. J. Weeks, U. R. Kees, S. Song, and I. M. Morison, “Silencing of Testin by Dense Biallelic Promoter Methylation Is the Most Common Molecular Event in Childhood Acute Lymphoblastic Leukaemia,” Molecular Cancer 9 (2010): 163.
- 12M. Wang, Q. Wang, W. J. Peng, et al., “Testin Is a Tumor Suppressor in Non-Small Cell Lung Cancer,” Oncology Reports 37, no. 2 (2017): 1027–1035.
- 13J. Zhu, X. Li, X. Kong, et al., “Testin Is a Tumor Suppressor and Prognostic Marker in Breast Cancer,” Cancer Science 103, no. 12 (2012): 2092–2101.
- 14B. Boeda, D. C. Briggs, T. Higgins, et al., “Tes, a Specific Mena Interacting Partner, Breaks the Rules for EVH1 Binding [J],” Molecular Cell 28, no. 6 (2007): 1071–1082.
- 15V. Sharma, M. Ichikawa, and H. H. Freeze, “Mannose Metabolism: More Than Meets the Eye,” Biochemical and Biophysical Research Communications 453, no. 2 (2014): 220–228.
- 16S. Torretta, A. Scagliola, L. Ricci, et al., “D-Mannose Suppresses Macrophage IL-1β Production,” Nature Communications 11, no. 1 (2020): 6343.
- 17D. Ito, H. Ito, T. Ideta, et al., “D-Mannose Administration Improves Autoimmune Hepatitis by Upregulating Regulatory T Cells [J],” Cellular Immunology 375 (2022): 104517.
- 18P. S. Gonzalez, J. O'prey, S. Cardaci, et al., “Mannose Impairs Tumour Growth and Enhances Chemotherapy,” Nature 563, no. 7733 (2018): 719–723.
- 19R. Zhang, Y. Yang, W. Dong, et al., “D-Mannose Facilitates Immunotherapy and Radiotherapy of Triple-Negative Breast Cancer via Degradation of PD-L1,” Proceedings of the National Academy of Sciences of the United States of America 119, no. 8 (2022): e2114851119.
- 20Y. Wang, S. Xie, and B. He, “Mannose Shows Antitumour Properties Against Lung Cancer via Inhibiting Proliferation, Promoting Cisplatin‑Mediated Apoptosis and Reducing Metastasis [J],” Molecular Medicine Reports 22, no. 4 (2020): 2957–2965.
- 21S. Okabe, Y. Tanaka, and A. Gotoh, “Effect of D-Mannose on Philadelphia Chromosome-Positive Leukemia Cells,” Cancer Biomarkers 34, no. 3 (2022): 337–346.
- 22R. Zhang, Z. Tian, Y. Xu, and L. Lv, “D-Mannose Promotes the Degradation of IDH2 Through Upregulation of RNF185 and Suppresses Breast Cancer,” Nutrition & Metabolism 21, no. 1 (2024): 5.
- 23R. Kyriakides, P. Jones, and B. K. Somani, “Role of D-Mannose in the Prevention of Recurrent Urinary Tract Infections: Evidence From a Systematic Review of the Literature,” European Urology Focus 7, no. 5 (2021): 1166–1169.
- 24Y. Yongbin, L. Jinghua, Z. Zhanxue, et al., “TES Was Epigenetically Silenced and Suppressed the Epithelial–Mesenchymal Transition in Breast Cancer,” Tumor Biology 35, no. 11 (2014): 11381–11389.
- 25H. Li, K. Huang, L. Gao, et al., “TES Inhibits Colorectal Cancer Progression Through Activation of p38,” Oncotarget 7, no. 29 (2016): 45819–45836.
- 26Y. Bai, Q. G. Zhang, and X.-H. Wang, “Downregulation of TES by Hypermethylation in Glioblastoma Reduces Cell Apoptosis and Predicts Poor Clinical Outcome,” European Journal of Medical Research 19 (2014): 66.
- 27L. Chêne, C. Giroud, F. Desgrandchamps, et al., “Extensive Analysis of the 7q31 Region in Human Prostate Tumors Supports TES as the Best Candidate Tumor Suppressor Gene,” International Journal of Cancer 111, no. 5 (2004): 798–804.
- 28T. E. Cooper, C. Teng, M. Howell, et al., “D-Mannose for Preventing and Treating Urinary Tract Infections [J],” Cochrane Database of Systematic Reviews 8, no. 8 (2022): Cd013608.
- 29Y. L. Deng, R. Liu, Z. D. Cai, et al., “Mannose Inhibits the Growth of Prostate Cancer Through a Mitochondrial Mechanism,” Asian Journal of Andrology 24, no. 5 (2022): 540–548.
- 30X. Dolcet, D. Llobet, J. Pallares, and X. Matias-Guiu, “NF-kB in Development and Progression of Human Cancer,” Virchows Archiv 446, no. 5 (2005): 475–482.
- 31X. Zhao, L. Li, S. Yuan, et al., “SPIB Acts as a Tumor Suppressor by Activating the NFkB and JNK Signaling Pathways Through MAP4K1 in Colorectal Cancer Cells [J],” Cellular Signalling 88 (2021): 110148.
- 32W. Wu, B. Ma, H. Ye, et al., “Millepachine, a Potential Topoisomerase II Inhibitor Induces Apoptosis via Activation of NF-κB Pathway in Ovarian Cancer,” Oncotarget 7, no. 32 (2016): 52281–52293.
- 33S. C. Sun, “The Non-Canonical NF-κB Pathway in Immunity and Inflammation,” Nature Reviews Immunology 17, no. 9 (2017): 545–558.
- 34T. Lawrence, “The Nuclear Factor NF- B Pathway in Inflammation,” Cold Spring Harbor Perspectives in Biology 1, no. 6 (2009): a001651.
- 35M. R. Zinatizadeh, B. Schock, G. M. Chalbatani, P. K. Zarandi, S. A. Jalali, and S. R. Miri, “The Nuclear Factor Kappa B (NF-kB) Signaling in Cancer Development and Immune Diseases,” Genes & Diseases 8, no. 3 (2021): 287–297.
- 36B. Hoesel and J. A. Schmid, “The Complexity of NF-κB Signaling in Inflammation and Cancer,” Molecular Cancer 12 (2013): 86.
- 37H. Yu, L. Lin, Z. Zhang, et al., “Targeting NF-κB Pathway for the Therapy of Diseases: Mechanism and Clinical Study [J],” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 209.