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1
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Leck LYW, Abd El-Aziz YS, McKelvey KJ, Park KC, Sahni S, Lane DJR, Skoda J, Jansson PJ. Cancer stem cells: Masters of all traits. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167549. [PMID: 39454969 DOI: 10.1016/j.bbadis.2024.167549] [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: 02/05/2024] [Revised: 10/01/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.
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Affiliation(s)
- Lionel Y W Leck
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia
| | - Yomna S Abd El-Aziz
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta, Egypt
| | - Kelly J McKelvey
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Kyung Chan Park
- Proteina Co., Ltd./Seoul National University, Seoul, South Korea
| | - Sumit Sahni
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia
| | - Darius J R Lane
- Melbourne Dementia Research Centre, The Florey Institute of Neuroscience & Mental Health, The University of Melbourne, Parkville, VIC, Australia
| | - Jan Skoda
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
| | - Patric J Jansson
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, Faculty of Medicine and Health, The University of Sydney, St Leonards, NSW, Australia; Cancer Drug Resistance & Stem Cell Program, School of Medical Science, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, Australia.
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2
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Sehgal M, Nayak SP, Sahoo S, Somarelli JA, Jolly MK. Mutually exclusive teams-like patterns of gene regulation characterize phenotypic heterogeneity along the noradrenergic-mesenchymal axis in neuroblastoma. Cancer Biol Ther 2024; 25:2301802. [PMID: 38230570 PMCID: PMC10795782 DOI: 10.1080/15384047.2024.2301802] [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: 09/08/2023] [Accepted: 01/01/2024] [Indexed: 01/18/2024] Open
Abstract
Neuroblastoma is the most frequent extracranial pediatric tumor and leads to 15% of all cancer-related deaths in children. Tumor relapse and therapy resistance in neuroblastoma are driven by phenotypic plasticity and heterogeneity between noradrenergic (NOR) and mesenchymal (MES) cell states. Despite the importance of this phenotypic plasticity, the dynamics and molecular patterns associated with these bidirectional cell-state transitions remain relatively poorly understood. Here, we analyze multiple RNA-seq datasets at both bulk and single-cell resolution, to understand the association between NOR- and MES-specific factors. We observed that NOR-specific and MES-specific expression patterns are largely mutually exclusive, exhibiting a "teams-like" behavior among the genes involved, reminiscent of our earlier observations in lung cancer and melanoma. This antagonism between NOR and MES phenotypes was also associated with metabolic reprogramming and with immunotherapy targets PD-L1 and GD2 as well as with experimental perturbations driving the NOR-MES and/or MES-NOR transition. Further, these "teams-like" patterns were seen only among the NOR- and MES-specific genes, but not in housekeeping genes, possibly highlighting a hallmark of network topology enabling cancer cell plasticity.
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Affiliation(s)
- Manas Sehgal
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | - Sonali Priyadarshini Nayak
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
- Max Planck School Matter to Life, University of Göttingen, Göttingen, Germany
| | - Sarthak Sahoo
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
| | | | - Mohit Kumar Jolly
- Department of Bioengineering, Indian Institute of Science, Bangalore, India
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3
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Köles L, Ribiczey P, Szebeni A, Kádár K, Zelles T, Zsembery Á. The Role of TRPM7 in Oncogenesis. Int J Mol Sci 2024; 25:719. [PMID: 38255793 PMCID: PMC10815510 DOI: 10.3390/ijms25020719] [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: 11/28/2023] [Revised: 12/30/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
This review summarizes the current understanding of the role of transient receptor potential melastatin-subfamily member 7 (TRPM7) channels in the pathophysiology of neoplastic diseases. The TRPM family represents the largest and most diverse group in the TRP superfamily. Its subtypes are expressed in virtually all human organs playing a central role in (patho)physiological events. The TRPM7 protein (along with TRPM2 and TRPM6) is unique in that it has kinase activity in addition to the channel function. Numerous studies demonstrate the role of TRPM7 chanzyme in tumorigenesis and in other tumor hallmarks such as proliferation, migration, invasion and metastasis. Here we provide an up-to-date overview about the possible role of TRMP7 in a broad range of malignancies such as tumors of the nervous system, head and neck cancers, malignant neoplasms of the upper gastrointestinal tract, colorectal carcinoma, lung cancer, neoplasms of the urinary system, breast cancer, malignant tumors of the female reproductive organs, prostate cancer and other neoplastic pathologies. Experimental data show that the increased expression and/or function of TRPM7 are observed in most malignant tumor types. Thus, TRPM7 chanzyme may be a promising target in tumor therapy.
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Affiliation(s)
- László Köles
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
| | - Polett Ribiczey
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
| | - Andrea Szebeni
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
| | - Kristóf Kádár
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
| | - Tibor Zelles
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
- Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, H-1083, Budapest, Hungary
| | - Ákos Zsembery
- Department of Oral Biology, Semmelweis University, H-1089 Budapest, Hungary; (L.K.); (A.S.); (K.K.); (T.Z.)
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4
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Otero-Sobrino Á, Blanco-Carlón P, Navarro-Aguadero MÁ, Gallardo M, Martínez-López J, Velasco-Estévez M. Mechanosensitive Ion Channels: Their Physiological Importance and Potential Key Role in Cancer. Int J Mol Sci 2023; 24:13710. [PMID: 37762011 PMCID: PMC10530364 DOI: 10.3390/ijms241813710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/29/2023] Open
Abstract
Mechanosensitive ion channels comprise a broad group of proteins that sense mechanical extracellular and intracellular changes, translating them into cation influx to adapt and respond to these physical cues. All cells in the organism are mechanosensitive, and these physical cues have proven to have an important role in regulating proliferation, cell fate and differentiation, migration and cellular stress, among other processes. Indeed, the mechanical properties of the extracellular matrix in cancer change drastically due to high cell proliferation and modification of extracellular protein secretion, suggesting an important contribution to tumor cell regulation. In this review, we describe the physiological significance of mechanosensitive ion channels, emphasizing their role in cancer and immunity, and providing compelling proof of the importance of continuing to explore their potential as new therapeutic targets in cancer research.
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Affiliation(s)
- Álvaro Otero-Sobrino
- H12O-CNIO Hematological Malignancies Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain; (Á.O.-S.); (P.B.-C.); (M.Á.N.-A.); (M.G.); (J.M.-L.)
- Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Pablo Blanco-Carlón
- H12O-CNIO Hematological Malignancies Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain; (Á.O.-S.); (P.B.-C.); (M.Á.N.-A.); (M.G.); (J.M.-L.)
- Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Miguel Ángel Navarro-Aguadero
- H12O-CNIO Hematological Malignancies Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain; (Á.O.-S.); (P.B.-C.); (M.Á.N.-A.); (M.G.); (J.M.-L.)
- Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Miguel Gallardo
- H12O-CNIO Hematological Malignancies Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain; (Á.O.-S.); (P.B.-C.); (M.Á.N.-A.); (M.G.); (J.M.-L.)
- Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Joaquín Martínez-López
- H12O-CNIO Hematological Malignancies Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain; (Á.O.-S.); (P.B.-C.); (M.Á.N.-A.); (M.G.); (J.M.-L.)
- Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
| | - María Velasco-Estévez
- H12O-CNIO Hematological Malignancies Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), 28029 Madrid, Spain; (Á.O.-S.); (P.B.-C.); (M.Á.N.-A.); (M.G.); (J.M.-L.)
- Department of Hematology, Hospital Universitario 12 de Octubre, Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
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5
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Kouba S, Hague F, Ahidouch A, Ouadid-Ahidouch H. Crosstalk between Ca2+ Signaling and Cancer Stemness: The Link to Cisplatin Resistance. Int J Mol Sci 2022; 23:ijms231810687. [PMID: 36142596 PMCID: PMC9503744 DOI: 10.3390/ijms231810687] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/07/2022] [Accepted: 09/10/2022] [Indexed: 11/28/2022] Open
Abstract
In the fight against cancer, therapeutic strategies using cisplatin are severely limited by the appearance of a resistant phenotype. While cisplatin is usually efficient at the beginning of the treatment, several patients endure resistance to this agent and face relapse. One of the reasons for this resistant phenotype is the emergence of a cell subpopulation known as cancer stem cells (CSCs). Due to their quiescent phenotype and self-renewal abilities, these cells have recently been recognized as a crucial field of investigation in cancer and treatment resistance. Changes in intracellular calcium (Ca2+) through Ca2+ channel activity are essential for many cellular processes such as proliferation, migration, differentiation, and survival in various cell types. It is now proved that altered Ca2+ signaling is a hallmark of cancer, and several Ca2+ channels have been linked to CSC functions and therapy resistance. Moreover, cisplatin was shown to interfere with Ca2+ homeostasis; thus, it is considered likely that cisplatin-induced aberrant Ca2+ signaling is linked to CSCs biology and, therefore, therapy failure. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to a range of pressures dictates the global degree of cisplatin resistance. However, if we can understand the molecular mechanisms linking Ca2+ to cisplatin-induced resistance and CSC behaviors, alternative and novel therapeutic strategies could be considered. In this review, we examine how cisplatin interferes with Ca2+ homeostasis in tumor cells. We also summarize how cisplatin induces CSC markers in cancer. Finally, we highlight the role of Ca2+ in cancer stemness and focus on how they are involved in cisplatin-induced resistance through the increase of cancer stem cell populations and via specific pathways.
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Affiliation(s)
- Sana Kouba
- Laboratoire de Physiologie Cellulaire et Moléculaire, Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France
| | - Frédéric Hague
- Laboratoire de Physiologie Cellulaire et Moléculaire, Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France
| | - Ahmed Ahidouch
- Laboratoire de Physiologie Cellulaire et Moléculaire, Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France
- Département de Biologie, Faculté des Sciences, Université Ibn Zohr, Agadir 81016, Morocco
| | - Halima Ouadid-Ahidouch
- Laboratoire de Physiologie Cellulaire et Moléculaire, Université de Picardie Jules Verne, UFR des Sciences, 33 Rue St Leu, 80039 Amiens, France
- Correspondence:
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6
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Xie T, Chen S, Hao J, Wu P, Gu X, Wei H, Li Z, Xiao J. Roles of calcium signaling in cancer metastasis to bone. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:445-462. [PMID: 36071984 PMCID: PMC9446157 DOI: 10.37349/etat.2022.00094] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/16/2022] [Indexed: 11/19/2022] Open
Abstract
Bone metastasis is a frequent complication for cancers and an important reason for the mortality in cancer patients. After surviving in bone, cancer cells can cause severe pain, life-threatening hypercalcemia, pathologic fractures, spinal cord compression, and even death. However, the underlying mechanisms of bone metastasis were not clear. The role of calcium (Ca2+) in cancer cell proliferation, migration, and invasion has been well established. Interestingly, emerging evidence indicates that Ca2+ signaling played a key role in bone metastasis, for it not only promotes cancer progression but also mediates osteoclasts and osteoblasts differentiation. Therefore, Ca2+ signaling has emerged as a novel therapeutical target for cancer bone metastasis treatments. Here, the role of Ca2+ channels and Ca2+-binding proteins including calmodulin and Ca2+-sensing receptor in bone metastasis, and the perspective of anti-cancer bone metastasis therapeutics via targeting the Ca2+ signaling pathway are summarized.
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Affiliation(s)
- Tianying Xie
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Sitong Chen
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Jiang Hao
- Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China
| | - Pengfei Wu
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, Hunan, China
| | - Xuelian Gu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China
| | - Haifeng Wei
- Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China
| | - Zhenxi Li
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China
| | - Jianru Xiao
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China; Department of Orthopedic Oncology, Shanghai Changzheng Hospital, Shanghai 200003, China
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7
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New Insights into TRP Ion Channels in Stem Cells. Int J Mol Sci 2022; 23:ijms23147766. [PMID: 35887116 PMCID: PMC9318110 DOI: 10.3390/ijms23147766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 12/10/2022] Open
Abstract
Transient receptor potential (TRP) ion channels are cationic permeable proteins located on the plasma membrane. TRPs are cellular sensors for perceiving diverse physical and/or chemical stimuli; thus, serving various critical physiological functions, including chemo-sensation, hearing, homeostasis, mechano-sensation, pain, taste, thermoregulation, vision, and even carcinogenesis. Dysregulated TRPs are found to be linked to many human hereditary diseases. Recent studies indicate that TRP ion channels are not only involved in sensory functions but are also implicated in regulating the biological characteristics of stem cells. In the present review, we summarize the expressions and functions of TRP ion channels in stem cells, including cancer stem cells. It offers an overview of the current understanding of TRP ion channels in stem cells.
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8
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Chen TM, Huang CM, Hsieh MS, Lin CS, Lee WH, Yeh CT, Liu SC. TRPM7 via calcineurin/NFAT pathway mediates metastasis and chemotherapeutic resistance in head and neck squamous cell carcinoma. Aging (Albany NY) 2022; 14:5250-5270. [PMID: 35771152 PMCID: PMC9271301 DOI: 10.18632/aging.204154] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 06/23/2022] [Indexed: 12/18/2022]
Abstract
The exact mechanisms of Head and neck squamous carcinoma (HNSCC) chemoresistance and metastatic transformation remain unclear. In recent decades, members of the transient receptor potential (TRP) channel family have been proposed as potential biomarkers and/or drug targets in cancer treatment. First, in a TCGA cohort of HNSCC, TRPM7 is highly expressed in cancer tissues, especially the expression in invasive cancer tissues is statistically significant (p>0.001). In GEO and TCGA cohort, patients with high expression of TRPM7 and NFATC2 have poor overall survival rates. The expression of TRPM7 and NFATC2 showed a positive correlation. Compared to human normal oral keratinocytes (hNOK), TRPM7 is overexpressed in FaDU, SAS, and TW2.6 cell lines. Similarly, patients with HNSCC exhibited higher TRPM7 expression than non-HNSCC subjects, and this high TRPM7 expression was associated with worse 5-year overall survival. Furthermore, TRPM7 inversely correlated with E-cadherin, but positively correlated with Vimentin, NANOG, and BMI-1 mRNA levels. Consistent with this, we demonstrated the overexpression of TRPM7 in cisplatin-resistant subjects, compared to the cisplatin-sensitive counterparts. Moreover, shRNA-mediated silencing of TRPM7 significantly suppressed the migration, invasion, colony formation, and tumorsphere formation of SAS cells, with associated downregulation of Snail, c-Myc, cyclin D1, SOX2, OCT4, and NANOG proteins expression. Finally, compared with the untreated wild-type SAS cells or cisplatin-treated cells, shTRPM7 alone or in combination with cisplatin significantly inhibited tumorsphere and colony formation. These findings serving as the basis for development of novel therapeutic strategies against metastasis and chemoresistance, while providing new insights into TRPM7 biology and activity in HNSCC.
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Affiliation(s)
- Tsung-Ming Chen
- Department of Otolaryngology-Head and Neck Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.,Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 11031, Taiwan
| | - Chih-Ming Huang
- Department of Otolaryngology, Taitung Mackay Memorial Hospital, Taitung City 950408, Taiwan.,Department of Nursing, Tajen University, Yanpu 90741, Pingtung County, Taiwan
| | - Ming-Shou Hsieh
- Department of Medical Research and Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City 235, Taiwan
| | - Chun-Shu Lin
- Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
| | - Wei-Hwa Lee
- Department of Pathology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan
| | - Chi-Tai Yeh
- Department of Medical Research and Education, Taipei Medical University - Shuang Ho Hospital, New Taipei City 235, Taiwan.,Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu City 30015, Taiwan
| | - Shao-Cheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan
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9
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Store-Operated Calcium Entry and Its Implications in Cancer Stem Cells. Cells 2022; 11:cells11081332. [PMID: 35456011 PMCID: PMC9032688 DOI: 10.3390/cells11081332] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/04/2022] [Accepted: 04/12/2022] [Indexed: 12/25/2022] Open
Abstract
Tumors are composed by a heterogeneous population of cells. Among them, a sub-population of cells, termed cancer stem cells, exhibit stemness features, such as self-renewal capabilities, disposition to differentiate to a more proliferative state, and chemotherapy resistance, processes that are all mediated by Ca2+. Ca2+ homeostasis is vital for several physiological processes, and alterations in the patterns of expressions of the proteins and molecules that modulate it have recently become a cancer hallmark. Store-operated Ca2+ entry is a major mechanism for Ca2+ entry from the extracellular medium in non-excitable cells that leads to increases in the cytosolic Ca2+ concentration required for several processes, including cancer stem cell properties. Here, we focus on the participation of STIM, Orai, and TRPC proteins, the store-operated Ca2+ entry key components, in cancer stem cell biology and tumorigenesis.
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10
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Burrell KL, Nguyen ND, Deering-Rice CE, Memon TA, Almestica-Roberts M, Rapp E, Serna SN, Lamb JG, Reilly CA. Dynamic Expression of Transient Receptor Potential Vanilloid-3 and Integrated Signaling with Growth Factor Pathways during Lung Epithelial Wound Repair following Wood Smoke Particle and Other Forms of Lung Cell Injury. Mol Pharmacol 2021; 100:295-307. [PMID: 34290137 PMCID: PMC11037451 DOI: 10.1124/molpharm.121.000280] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/25/2021] [Indexed: 11/22/2022] Open
Abstract
Prior studies revealed increased expression of the transient receptor potential vanilloid-3 (TRPV3) ion channel after wood smoke particulate matter (WSPM) treatment of human bronchial epithelial cells (HBECs). TRPV3 attenuated pathologic endoplasmic reticulum stress and cytotoxicity mediated by transient receptor potential ankyrin-1. Here, the basis for how TRPV3 expression is regulated by cell injury and the effects this has on HBEC physiology and WSPM-induced airway remodeling in mice was investigated. TRPV3 mRNA was rapidly increased in HBECs treated with WSPM and after monolayer damage caused by tryptic disruption, scratch wounding, and cell passaging. TRPV3 mRNA abundance varied with time, and stimulated expression occurred independent of new protein synthesis. Overexpression of TRPV3 in HBECs reduced cell migration and wound repair while enhancing cell adhesion. This phenotype correlated with disrupted mRNA expression of ligands of the epidermal growth factor, tumor growth factor-β, and frizzled receptors. Accordingly, delayed wound repair by TRPV3 overexpressing cells was reversed by growth factor supplementation. In normal HBECs, TRPV3 upregulation was triggered by exogenous growth factor supplementation and was attenuated by inhibitors of growth factor receptor signaling. In mice, subacute oropharyngeal instillation with WSPM also promoted TRPV3 mRNA expression and epithelial remodeling, which was attenuated by TRPV3 antagonist pre- and cotreatment. This latter effect may be the consequence of antagonist-induced TRPV3 expression. These findings provide insights into the roles of TRPV3 in lung epithelial cells under basal and dynamic states, as well as highlight potential roles for TRPV3 ligands in modulating epithelial damage/repair. SIGNIFICANCE STATEMENT: Coordinated epithelial repair is essential for the maintenance of the airways, with deficiencies and exaggerated repair associated with adverse consequences to respiratory health. This study shows that TRPV3, an ion channel, is involved in coordinating repair through integrated repair signaling pathways, wherein TRPV3 expression is upregulated immediately after injury and returns to basal levels as cells complete the repair process. TRPV3 may be a novel target for understanding and/or treating conditions in which airway/lung epithelial repair is not properly orchestrated.
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Affiliation(s)
- Katherine L Burrell
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Nam D Nguyen
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Cassandra E Deering-Rice
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Tosifa A Memon
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Marysol Almestica-Roberts
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Emmanuel Rapp
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Samantha N Serna
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - John G Lamb
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
| | - Christopher A Reilly
- Department of Pharmacology and Toxicology, Center for Human Toxicology, University of Utah, Salt Lake City, Utah
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11
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Sharma A, Ramena GT, Elble RC. Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy. Biomedicines 2021; 9:1077. [PMID: 34572262 PMCID: PMC8466575 DOI: 10.3390/biomedicines9091077] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/15/2021] [Accepted: 07/18/2021] [Indexed: 02/07/2023] Open
Abstract
Intracellular Ca2+ distribution is a tightly regulated process. Numerous Ca2+ chelating, storage, and transport mechanisms are required to maintain normal cellular physiology. Ca2+-binding proteins, mainly calmodulin and calbindins, sequester free intracellular Ca2+ ions and apportion or transport them to signaling hubs needing the cations. Ca2+ channels, ATP-driven pumps, and exchangers assist the binding proteins in transferring the ions to and from appropriate cellular compartments. Some, such as the endoplasmic reticulum, mitochondria, and lysosomes, act as Ca2+ repositories. Cellular Ca2+ homeostasis is inefficient without the active contribution of these organelles. Moreover, certain key cellular processes also rely on inter-organellar Ca2+ signaling. This review attempts to encapsulate the structure, function, and regulation of major intracellular Ca2+ buffers, sensors, channels, and signaling molecules before highlighting how cancer cells manipulate them to survive and thrive. The spotlight is then shifted to the slow pace of translating such research findings into anticancer therapeutics. We use the PubMed database to highlight current clinical studies that target intracellular Ca2+ signaling. Drug repurposing and improving the delivery of small molecule therapeutics are further discussed as promising strategies for speeding therapeutic development in this area.
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Affiliation(s)
- Aarushi Sharma
- Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
| | - Grace T. Ramena
- Department of Aquaculture, University of Arkansas, Pine Bluff, AR 71601, USA;
| | - Randolph C. Elble
- Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA;
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12
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Transient Receptor Potential Channels in the Epithelial-to-Mesenchymal Transition. Int J Mol Sci 2021; 22:ijms22158188. [PMID: 34360952 PMCID: PMC8348042 DOI: 10.3390/ijms22158188] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/19/2021] [Accepted: 07/27/2021] [Indexed: 12/14/2022] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) is a strictly regulated process that is indispensable for normal development, but it can result in fibrosis and cancer progression. It encompasses a complete alteration of the cellular transcriptomic profile, promoting the expression of genes involved in cellular migration, invasion and proliferation. Extracellular signaling factors driving the EMT process require secondary messengers to convey their effects to their targets. Due to its remarkable properties, calcium represents an ideal candidate to translate molecular messages from receptor to effector. Therefore, calcium-permeable ion channels that facilitate the influx of extracellular calcium into the cytosol can exert major influences on cellular phenotype. Transient receptor potential (TRP) channels represent a superfamily of non-selective cation channels that decode physical and chemical stimuli into cellular behavior. Their role as cellular sensors renders them interesting proteins to study in the context of phenotypic transitions, such as EMT. In this review, we elaborate on the current knowledge regarding TRP channel expression and activity in cellular phenotype and EMT.
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13
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Farina AR, Cappabianca LA, Zelli V, Sebastiano M, Mackay AR. Mechanisms involved in selecting and maintaining neuroblastoma cancer stem cell populations, and perspectives for therapeutic targeting. World J Stem Cells 2021; 13:685-736. [PMID: 34367474 PMCID: PMC8316860 DOI: 10.4252/wjsc.v13.i7.685] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Pediatric neuroblastomas (NBs) are heterogeneous, aggressive, therapy-resistant embryonal tumours that originate from cells of neural crest (NC) origin and in particular neuroblasts committed to the sympathoadrenal progenitor cell lineage. Therapeutic resistance, post-therapeutic relapse and subsequent metastatic NB progression are driven primarily by cancer stem cell (CSC)-like subpopulations, which through their self-renewing capacity, intermittent and slow cell cycles, drug-resistant and reversibly adaptive plastic phenotypes, represent the most important obstacle to improving therapeutic outcomes in unfavourable NBs. In this review, dedicated to NB CSCs and the prospects for their therapeutic eradication, we initiate with brief descriptions of the unique transient vertebrate embryonic NC structure and salient molecular protagonists involved NC induction, specification, epithelial to mesenchymal transition and migratory behaviour, in order to familiarise the reader with the embryonic cellular and molecular origins and background to NB. We follow this by introducing NB and the potential NC-derived stem/progenitor cell origins of NBs, before providing a comprehensive review of the salient molecules, signalling pathways, mechanisms, tumour microenvironmental and therapeutic conditions involved in promoting, selecting and maintaining NB CSC subpopulations, and that underpin their therapy-resistant, self-renewing metastatic behaviour. Finally, we review potential therapeutic strategies and future prospects for targeting and eradication of these bastions of NB therapeutic resistance, post-therapeutic relapse and metastatic progression.
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Affiliation(s)
- Antonietta Rosella Farina
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Lucia Annamaria Cappabianca
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Veronica Zelli
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Michela Sebastiano
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy
| | - Andrew Reay Mackay
- Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, L'Aquila 67100, AQ, Italy.
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14
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From Channels to Canonical Wnt Signaling: A Pathological Perspective. Int J Mol Sci 2021; 22:ijms22094613. [PMID: 33924772 PMCID: PMC8125460 DOI: 10.3390/ijms22094613] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Wnt signaling is an important pathway mainly active during embryonic development and controlling cell proliferation. This regulatory pathway is aberrantly activated in several human diseases. Ion channels are known modulators of several important cellular functions ranging from the tuning of the membrane potential to modulation of intracellular pathways, in particular the influence of ion channels in Wnt signaling regulation has been widely investigated. This review will discuss the known links between ion channels and canonical Wnt signaling, focusing on their possible roles in human metabolic diseases, neurological disorders, and cancer.
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15
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Meng S, Alanazi R, Ji D, Bandura J, Luo ZW, Fleig A, Feng ZP, Sun HS. Role of TRPM7 kinase in cancer. Cell Calcium 2021; 96:102400. [PMID: 33784560 DOI: 10.1016/j.ceca.2021.102400] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/18/2021] [Accepted: 03/20/2021] [Indexed: 01/09/2023]
Abstract
Cancer is the second leading cause of death worldwide and accounted for an estimated 9.6 million deaths, or 1 in 6 deaths, in 2018. Despite recent advances in cancer prevention, diagnosis, and treatment strategies, the burden of this disease continues to grow with each year, with dire physical, emotional, and economic consequences for all levels of society. Classic characteristics of cancer include rapid, uncontrolled cell proliferation and spread of cancerous cells to other parts of the body, a process known as metastasis. Transient receptor potential melastatin 7 (TRPM7), a Ca2+- and Mg2+-permeable nonselective divalent cation channel defined by the atypical presence of an α-kinase within its C-terminal domain, has been implicated, due to its modulation of Ca2+ and Mg2+ influx, in a wide variety of physiological and pathological processes, including cancer. TRPM7 is overexpressed in several cancer types and has been shown to variably increase cellular proliferation, migration, and invasion of tumour cells. However, the relative contribution of TRPM7 kinase domain activity to cancer as opposed to ion flux through its channel pore remains an area of active discovery. In this review, we describe the specific role of the TRPM7 kinase domain in cancer processes as well as mechanisms of regulation and inhibition of the kinase domain.
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Affiliation(s)
- Selena Meng
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Rahmah Alanazi
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Delphine Ji
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Julia Bandura
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Zheng-Wei Luo
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada
| | - Andrea Fleig
- Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine and Cancer Center at the University of Hawaii, Honolulu, HI, 96720, USA
| | - Zhong-Ping Feng
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
| | - Hong-Shuo Sun
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Department of Pharmacology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
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16
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Lavanderos B, Silva I, Cruz P, Orellana-Serradell O, Saldías MP, Cerda O. TRP Channels Regulation of Rho GTPases in Brain Context and Diseases. Front Cell Dev Biol 2020; 8:582975. [PMID: 33240883 PMCID: PMC7683514 DOI: 10.3389/fcell.2020.582975] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
Neurological and neuropsychiatric disorders are mediated by several pathophysiological mechanisms, including developmental and degenerative abnormalities caused primarily by disturbances in cell migration, structural plasticity of the synapse, and blood-vessel barrier function. In this context, critical pathways involved in the pathogenesis of these diseases are related to structural, scaffolding, and enzymatic activity-bearing proteins, which participate in Ca2+- and Ras Homologs (Rho) GTPases-mediated signaling. Rho GTPases are GDP/GTP binding proteins that regulate the cytoskeletal structure, cellular protrusion, and migration. These proteins cycle between GTP-bound (active) and GDP-bound (inactive) states due to their intrinsic GTPase activity and their dynamic regulation by GEFs, GAPs, and GDIs. One of the most important upstream inputs that modulate Rho GTPases activity is Ca2+ signaling, positioning ion channels as pivotal molecular entities for Rho GTPases regulation. Multiple non-selective cationic channels belonging to the Transient Receptor Potential (TRP) family participate in cytoskeletal-dependent processes through Ca2+-mediated modulation of Rho GTPases. Moreover, these ion channels have a role in several neuropathological events such as neuronal cell death, brain tumor progression and strokes. Although Rho GTPases-dependent pathways have been extensively studied, how they converge with TRP channels in the development or progression of neuropathologies is poorly understood. Herein, we review recent evidence and insights that link TRP channels activity to downstream Rho GTPase signaling or modulation. Moreover, using the TRIP database, we establish associations between possible mediators of Rho GTPase signaling with TRP ion channels. As such, we propose mechanisms that might explain the TRP-dependent modulation of Rho GTPases as possible pathways participating in the emergence or maintenance of neuropathological conditions.
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Affiliation(s)
- Boris Lavanderos
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Ian Silva
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Pablo Cruz
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Octavio Orellana-Serradell
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - María Paz Saldías
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
| | - Oscar Cerda
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.,Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile.,The Wound Repair, Treatment and Health (WoRTH) Initiative, Santiago, Chile
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Vrenken KS, Vervoort BMT, van Ingen Schenau DS, Derks YHW, van Emst L, Grytsenko PG, Middelbeek JAJ, van Leeuwen FN. The transcriptional repressor SNAI2 impairs neuroblastoma differentiation and inhibits response to retinoic acid therapy. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165644. [PMID: 31862304 DOI: 10.1016/j.bbadis.2019.165644] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 12/03/2019] [Accepted: 12/14/2019] [Indexed: 02/07/2023]
Abstract
Neuroblastoma is the most common extracranial solid tumor in children and originates from poorly differentiated neural crest progenitors. High-risk neuroblastoma patients frequently present with metastatic disease at diagnosis. Despite intensive treatment, patients often develop refractory disease characterized by poorly differentiated, therapy resistant cells. Although adjuvant therapy using retinoic acid (RA)-induced differentiation may increase event-free survival, in the majority of cases response to RA-therapy is inadequate. Consequently, current research aims to identify novel therapeutic targets that enhance the sensitivity to RA and induce neuroblastoma cell differentiation. The similarities between neural crest development and neuroblastoma progression provide an appealing starting point. During neural crest development the EMT-transcription factor SNAI2 plays an important role in neural crest specification as well as neural crest cell migration and survival. Here, we report that CRISPR/Cas9 mediated deletion as well as shRNA mediated knockdown of the EMT-transcription factor SNAI2 promotes cellular differentiation in a variety of neuroblastoma models. By comparing mRNA expression data from independent patient cohorts, we show that a SNAI2 activity-based gene expression signature significantly correlates with event-free survival. Loss of SNAI2 function reduces self-renewal, 3D invasion as well as metastatic spread in vivo, while strongly sensitizing neuroblastoma cells to RA-induced growth inhibition. Together, our data demonstrate that SNAI2 maintains progenitor-like features in neuroblastoma cells while interfering with RA-induced growth inhibition. We propose that targeting gene regulatory circuits, such as those controlling SNAI2 function, may allow reversion of RA-therapy resistant neuroblastoma cells to a more differentiated and therapy responsive phenotype.
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Affiliation(s)
- Kirsten S Vrenken
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Britt M T Vervoort
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Dorette S van Ingen Schenau
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Yvonne H W Derks
- Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Liesbeth van Emst
- Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Pavlo G Grytsenko
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jeroen A J Middelbeek
- Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Frank N van Leeuwen
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
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18
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Bahmad HF, Chamaa F, Assi S, Chalhoub RM, Abou-Antoun T, Abou-Kheir W. Cancer Stem Cells in Neuroblastoma: Expanding the Therapeutic Frontier. Front Mol Neurosci 2019; 12:131. [PMID: 31191243 PMCID: PMC6546065 DOI: 10.3389/fnmol.2019.00131] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents.
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Affiliation(s)
- Hisham F Bahmad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Farah Chamaa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Sahar Assi
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Reda M Chalhoub
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Tamara Abou-Antoun
- Department of Pharmaceutical Sciences, School of Pharmacy, Lebanese American University, Byblos, Lebanon
| | - Wassim Abou-Kheir
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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O'Reilly D, Buchanan P. Calcium channels and cancer stem cells. Cell Calcium 2019; 81:21-28. [PMID: 31163289 DOI: 10.1016/j.ceca.2019.05.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 05/21/2019] [Accepted: 05/21/2019] [Indexed: 12/24/2022]
Abstract
Cancer stem cells (CSC's) have emerged as a key area of investigation due to associations with cancer development and treatment resistance, related to their ability to remain quiescent, self-renew and terminally differentiate. Targeting CSC's in addition to the tumour bulk could ensure complete removal of the cancer, lessening the risk of relapse and improving patient survival. Understanding the mechanisms supporting the functions of CSC's is essential to highlight targets for the development of therapeutic strategies. Changes in intracellular calcium through calcium channel activity is fundamental for integral cellular processes such as proliferation, migration, differentiation and survival in a range of cell types, under both normal and pathological conditions. Here in we highlight how calcium channels represent a key mechanism involved in CSC function. It is clear that expression and or function of a number of channels involved in calcium entry and intracellular store release are altered in CSC's. Correlating with aberrant proliferation, self-renewal and differentiation, which in turn promoted cancer progression and treatment resistance. Research outlined has demonstrated that targeting altered calcium channels in CSC populations can reduce their stem properties and induce terminal differentiation, sensitising them to existing cancer treatments. Overall this highlights calcium channels as emerging novel targets for CSC therapies.
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Affiliation(s)
- Debbie O'Reilly
- National Institute of Cellular Biotechnology, Dublin City University, Dublin, Ireland; School of Nursing and Human science, Dublin City University, Dublin, Ireland
| | - Paul Buchanan
- National Institute of Cellular Biotechnology, Dublin City University, Dublin, Ireland; School of Nursing and Human science, Dublin City University, Dublin, Ireland.
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20
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Broertjes J, Klarenbeek J, Habani Y, Langeslag M, Jalink K. TRPM7 residue S1269 mediates cAMP dependence of Ca2+ influx. PLoS One 2019; 14:e0209563. [PMID: 30615643 PMCID: PMC6322742 DOI: 10.1371/journal.pone.0209563] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 12/07/2018] [Indexed: 02/06/2023] Open
Abstract
The nonspecific divalent cation channel TRPM7 (transient receptor potential-melastatin-like 7) is involved in many Ca2+ and Mg2+-dependent cellular processes, including survival, proliferation and migration. TRPM7 expression predicts metastasis and recurrence in breast cancer and several other cancers. In cultured cells, it can induce an invasive phenotype by promoting Ca2+-mediated epithelial-mesenchymal transition. We previously showed that in neuroblastoma cells that overexpress TRPM7 moderately, stimulation with Ca2+-mobilizing agonists leads to a characteristic sustained influx of Ca2+. Here we report that sustained influx through TRPM7 is abruptly abrogated by elevating intracellular levels of cyclic adenosine monophosphate (cAMP). Using pharmacological inhibitors and overexpression studies we show that this blockage is mediated by the cAMP effector Protein Kinase A (PKA). Mutational analysis demonstrates that the Serine residue S1269, which is present proximal to the coiled-coil domain within the protein c-terminus, is responsible for sensitivity to cAMP.
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Affiliation(s)
- Jorrit Broertjes
- Division of Cell Biology I, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jeffrey Klarenbeek
- Division of Cell Biology I, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Yasmin Habani
- Division of Cell Biology I, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Michiel Langeslag
- Division of Cell Biology I, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Kees Jalink
- Division of Cell Biology I, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- * E-mail:
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21
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Kamermans A, Planting KE, Jalink K, van Horssen J, de Vries HE. Reactive astrocytes in multiple sclerosis impair neuronal outgrowth through TRPM7-mediated chondroitin sulfate proteoglycan production. Glia 2018; 67:68-77. [PMID: 30453391 PMCID: PMC6587975 DOI: 10.1002/glia.23526] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/08/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), characterized by inflammation‐mediated demyelination, axonal injury and neurodegeneration. The mechanisms underlying impaired neuronal function are not fully understood, but evidence is accumulating that the presence of the gliotic scar produced by reactive astrocytes play a critical role in these detrimental processes. Here, we identified astrocytic Transient Receptor Potential cation channel, subfamily M, member 7 (TRPM7), a Ca2+‐permeable nonselective cation channel, as a novel player in the formation of a gliotic scar. TRPM7 was found to be highly expressed in reactive astrocytes within well‐characterized MS lesions and upregulated in primary astrocytes under chronic inflammatory conditions. TRPM7 overexpressing astrocytes impaired neuronal outgrowth in vitro by increasing the production of chondroitin sulfate proteoglycans, a key component of the gliotic scar. These findings indicate that astrocytic TRPM7 is a critical regulator of the formation of a gliotic scar and provide a novel mechanism by which reactive astrocytes affect neuronal outgrowth.
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Affiliation(s)
- Alwin Kamermans
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Kirsten E Planting
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Kees Jalink
- Department of Cell Biology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jack van Horssen
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Helga E de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
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22
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TRPM7 controls mesenchymal features of breast cancer cells by tensional regulation of SOX4. Biochim Biophys Acta Mol Basis Dis 2018; 1864:2409-2419. [DOI: 10.1016/j.bbadis.2018.04.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 04/13/2018] [Accepted: 04/18/2018] [Indexed: 01/04/2023]
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23
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Yee NS. Role of TRPM7 in Cancer: Potential as Molecular Biomarker and Therapeutic Target. Pharmaceuticals (Basel) 2017; 10:39. [PMID: 28379203 PMCID: PMC5490396 DOI: 10.3390/ph10020039] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Revised: 02/22/2017] [Accepted: 03/29/2017] [Indexed: 12/31/2022] Open
Abstract
The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed ion channel with intrinsic kinase activity. Molecular and electrophysiological analyses of the structure and activity of TRPM7 have revealed functional coupling of its channel and kinase activity. Studies have indicated the important roles of TRPM7 channel-kinase in fundamental cellular processes, physiological responses, and embryonic development. Accumulating evidence has shown that TRPM7 is aberrantly expressed and/or activated in human diseases including cancer. TRPM7 plays a variety of functional roles in cancer cells including survival, cell cycle progression, proliferation, growth, migration, invasion, and epithelial-mesenchymal transition (EMT). Data from a study using mouse xenograft of human cancer show that TRPM7 is required for tumor growth and metastasis. The aberrant expression of TRPM7 and its genetic mutations/polymorphisms have been identified in various types of carcinoma. Chemical modulators of TRPM7 channel produced inhibition of proliferation, growth, migration, invasion, invadosome formation, and markers of EMT in cancer cells. Taken together, these studies suggest the potential value of exploiting TRPM7 channel-kinase as a molecular biomarker and therapeutic target in human malignancies.
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Affiliation(s)
- Nelson S Yee
- Division of Hematology-Oncology, Department of Medicine, PennState Health Milton S. Hershey Medical Center, Program of Experimental Therapeutics, PennState Cancer Institute, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
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Rybarczyk P, Vanlaeys A, Brassart B, Dhennin-Duthille I, Chatelain D, Sevestre H, Ouadid-Ahidouch H, Gautier M. The Transient Receptor Potential Melastatin 7 Channel Regulates Pancreatic Cancer Cell Invasion through the Hsp90α/uPA/MMP2 pathway. Neoplasia 2017; 19:288-300. [PMID: 28284058 PMCID: PMC5345960 DOI: 10.1016/j.neo.2017.01.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 01/05/2017] [Accepted: 01/13/2017] [Indexed: 12/28/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a very poor prognosis. There is an urgent need to better understand the molecular mechanisms that regulate PDAC cell aggressiveness. The transient receptor potential melastatin 7 (TRPM7) is a nonselective cationic channel that mainly conducts Ca2+ and Mg2+. TRPM7 is overexpressed in numerous malignancies including PDAC. In the present study, we used the PANC-1 and MIA PaCa-2 cell lines to specifically assess the role of TRPM7 in cell invasion and matrix metalloproteinase secretion. We show that TRPM7 regulates Mg2+ homeostasis and constitutive cation entry in both PDAC cell lines. Moreover, cell invasion is strongly reduced by TRPM7 silencing without affecting the cell viability. Conditioned media were further studied, by gel zymography, to detect matrix metalloproteinase (MMP) secretion in PDAC cells. Our results show that MMP-2, urokinase plasminogen activator (uPA), and heat-shock protein 90α (Hsp90α) secretions are significantly decreased in TRPM7-deficient PDAC cells. Moreover, TRPM7 expression in human PDAC lymph node metastasis is correlated to the channel expression in primary tumor. Taken together, our results show that TRPM7 is involved in PDAC cell invasion through regulation of Hsp90α/uPA/MMP-2 proteolytic axis, confirming that this channel could be a promising biomarker and possibly a target for PDAC metastasis therapy.
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Affiliation(s)
- Pierre Rybarczyk
- Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231)
| | - Alison Vanlaeys
- Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231)
| | - Bertrand Brassart
- SFR CAP-Santé (FED 4231); UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Université de Reims Champagne Ardenne (URCA), F-51095 Reims, France
| | - Isabelle Dhennin-Duthille
- Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231)
| | - Denis Chatelain
- Service d'anatomie pathologique, CHU d'Amiens, Université de Picardie Jules Verne, F-80000 Amiens, France, France
| | - Henri Sevestre
- Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231); Service d'anatomie pathologique, CHU d'Amiens, Université de Picardie Jules Verne, F-80000 Amiens, France, France
| | - Halima Ouadid-Ahidouch
- Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231)
| | - Mathieu Gautier
- Laboratoire de Physiologie Cellulaire et Moléculaire-EA4667, UFR Sciences, Université de Picardie Jules Verne, F-80039 Amiens, France; SFR CAP-Santé (FED 4231).
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25
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The TRPM7 interactome defines a cytoskeletal complex linked to neuroblastoma progression. Eur J Cell Biol 2016; 95:465-474. [DOI: 10.1016/j.ejcb.2016.06.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 06/16/2016] [Accepted: 06/23/2016] [Indexed: 01/27/2023] Open
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26
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Chen Y, Yu Y, Sun S, Wang Z, Liu P, Liu S, Jiang J. Bradykinin promotes migration and invasion of hepatocellular carcinoma cells through TRPM7 and MMP2. Exp Cell Res 2016; 349:68-76. [DOI: 10.1016/j.yexcr.2016.09.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 09/26/2016] [Accepted: 09/28/2016] [Indexed: 12/26/2022]
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27
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Breuksch I, Weinert M, Brenner W. The role of extracellular calcium in bone metastasis. J Bone Oncol 2016; 5:143-145. [PMID: 27761377 PMCID: PMC5063220 DOI: 10.1016/j.jbo.2016.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 06/15/2016] [Accepted: 06/20/2016] [Indexed: 12/17/2022] Open
Abstract
This review summarizes the role of extracellular calcium, as found present in the bone tissue, in the process of bone metastasis.
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Key Words
- AKT, AKT8 virus oncogene cellular homolog
- BMP's, bone morphogenetic proteins
- Bone metastasis
- COPD, chronic obstructive pulmonary disease
- CaSR
- CaSR, calcium-sensing receptor
- Calcium
- ERK, extracellular signal-regulated kinase
- ET-1, endothelin-1
- FGF, fibroblast growth factor
- IGF, insulin-like growth factor
- Ion channels
- JNK, jun N-terminal kinase
- M-CSF, macrophage colony-stimulating factor
- MAPK, mitogen-activated protein kinase
- PDGF, platelet-derived growth factor
- PGE-2, prostaglandin E-2
- PKA, protein kinase A
- PLC, phospholipase C
- PSA, prostate specific antigen
- PTEN, phosphatase and tensin homolog deleted on chromosome 10
- PTHrP, parathyroid hormone-related protein
- RANK, receptor activator of NF-κB
- RANKL, receptor activator of NF-κB ligand
- SK3, small conductance calcium-activated potassium channel 3
- TGFβ, transforming growth factor beta
- TRP, transient receptor potential
- cAMP, cyclic adenosine monophosphate
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Vrenken KS, Jalink K, van Leeuwen FN, Middelbeek J. Beyond ion-conduction: Channel-dependent and -independent roles of TRP channels during development and tissue homeostasis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1436-46. [DOI: 10.1016/j.bbamcr.2015.11.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 10/26/2015] [Accepted: 11/11/2015] [Indexed: 01/09/2023]
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29
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Kim BJ, Hong C. Role of transient receptor potential melastatin type 7 channel in gastric cancer. Integr Med Res 2016; 5:124-130. [PMID: 28462107 PMCID: PMC5381434 DOI: 10.1016/j.imr.2016.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 04/01/2016] [Accepted: 04/05/2016] [Indexed: 01/11/2023] Open
Abstract
Transient receptor potential (TRP) proteins are a family of ion channels, which are responsible for a wide array of cellular functions. In particular, TRP melastatin type (TRPM) 7 is expressed everywhere and permeable to divalent cations such as Mg2+ and Ca2+. It contains a channel and a kinase domain. Recent studies indicate that activation of TRPM7 plays an important role in the growth and survival of gastric cancer cells. In this review, we describe and discuss the findings of recent studies that have provided novel insights of the relation between TRPM7 and gastric cancer.
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Affiliation(s)
- Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan, Korea
- Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Yangsan, Korea
| | - Chansik Hong
- Department of Physiology, Seoul National University, College of Medicine, Seoul, Korea
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Shapovalov G, Ritaine A, Skryma R, Prevarskaya N. Role of TRP ion channels in cancer and tumorigenesis. Semin Immunopathol 2016; 38:357-69. [PMID: 26842901 DOI: 10.1007/s00281-015-0525-1] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 09/03/2015] [Indexed: 12/12/2022]
Abstract
Transient receptor potential (TRP) channels are recently identified proteins that form a versatile family of ion channels, the majority of which are calcium permeable and exhibit complex regulatory patterns with sensitivity to multiple environmental factors. While this sensitivity has captured early attention, leading to recognition of TRP channels as environmental and chemical sensors, many later studies concentrated on the regulation of intracellular calcium by TRP channels. Due to mutations, dysregulation of ion channel gating or expression levels, normal spatiotemporal patterns of local Ca(2+) distribution become distorted. This causes deregulation of downstream effectors sensitive to changes in Ca(2+) homeostasis that, in turn, promotes pathophysiological cancer hallmarks, such as enhanced survival, proliferation and invasion. These observations give rise to the appreciation of the important contributions that TRP channels make to many cellular processes controlling cell fate and positioning these channels as important players in cancer regulation. This review discusses the accumulated scientific knowledge focused on TRP channel involvement in regulation of cell fate in various transformed tissues.
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Affiliation(s)
- George Shapovalov
- Inserm U1003, Equipe Labellisee par la Ligue Nationale Contre le Cancer, Universite de Sciences et Technologies de Lille (USTL), F-59655, Villeneuve d'Ascq, France.,Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France
| | - Abigael Ritaine
- Inserm U1003, Equipe Labellisee par la Ligue Nationale Contre le Cancer, Universite de Sciences et Technologies de Lille (USTL), F-59655, Villeneuve d'Ascq, France.,Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France
| | - Roman Skryma
- Inserm U1003, Equipe Labellisee par la Ligue Nationale Contre le Cancer, Universite de Sciences et Technologies de Lille (USTL), F-59655, Villeneuve d'Ascq, France.,Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France
| | - Natalia Prevarskaya
- Inserm U1003, Equipe Labellisee par la Ligue Nationale Contre le Cancer, Universite de Sciences et Technologies de Lille (USTL), F-59655, Villeneuve d'Ascq, France. .,Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille I Sciences et Technologies, Villeneuve d'Ascq, France.
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31
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Schäfer S, Ferioli S, Hofmann T, Zierler S, Gudermann T, Chubanov V. Mibefradil represents a new class of benzimidazole TRPM7 channel agonists. Pflugers Arch 2015; 468:623-34. [PMID: 26669310 DOI: 10.1007/s00424-015-1772-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 12/02/2015] [Accepted: 12/04/2015] [Indexed: 01/16/2023]
Abstract
Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a bi-functional protein comprising an ion channel moiety covalently linked to a protein kinase domain. Currently, the prevailing view is that a decrease in the cytosolic Mg(2+) concentration leads to activation of divalent cation-selective TRPM7 currents. TRPM7 plays a role in immune responses, hypotension, tissue fibrosis, and tumor progression and, therefore, represents a new promising therapeutic target. Because of the dearth of pharmacological tools, our mechanistic understanding of the role of TRPM7 in physiology and pathophysiology still lags behind. Therefore, we have recently carried out a high throughput screen for small-molecule activators of TRPM7. We have characterized the phenanthrene naltriben as a first stimulatory agonist of the TRPM7 channel. Surprisingly, the effect of naltriben on TRPM7 was found to be unaffected by the physiological levels of cytosolic Mg(2+). Here, we demonstrate that mibefradil and NNC 50-0396, two benzimidazole relatives of the TRPM7 inhibitor NS8593, are positive modulators of TRPM7. Using Ca(2+) imaging and the patch-clamp technique, we show that mibefradil activates TRPM7-mediated Ca(2+) entry and whole-cell currents. The response to mibefradil was fast, reversible, and reproducible. In contrast to naltriben, mibefradil efficiently activates TRPM7 currents only at physiological intracellular Mg(2+) concentrations, and its stimulatory effect was fully abrogated by high internal Mg(2+) levels. Consequently, a TRPM7 variant harboring a gain-of-function mutation was insensitive to further mibefradil activation. Finally, we observed that the effect of mibefradil was selective for TRPM7 when various TRP channels were tested. Taken together, mibefradil acts as a Mg(2+)-regulated agonist of the TRPM7 channel and, hence, uncovers a new class of TRPM7 agonists.
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Affiliation(s)
- Sebastian Schäfer
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany
| | - Silvia Ferioli
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany
| | - Thomas Hofmann
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany
| | - Susanna Zierler
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany
| | - Thomas Gudermann
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany
- Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany
| | - Vladimir Chubanov
- Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, 80336, Munich, Germany.
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32
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Smani T, Shapovalov G, Skryma R, Prevarskaya N, Rosado JA. Functional and physiopathological implications of TRP channels. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2015; 1853:1772-82. [DOI: 10.1016/j.bbamcr.2015.04.016] [Citation(s) in RCA: 289] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 04/22/2015] [Accepted: 04/24/2015] [Indexed: 10/23/2022]
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