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Cheng J, Zeng M, Peng B, Li P, Zhao S. Transient receptor potential vanilloid-1 (TRPV1) channels act as suppressors of the growth of glioma. Brain Res Bull 2024; 211:110950. [PMID: 38631651 DOI: 10.1016/j.brainresbull.2024.110950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 04/03/2024] [Accepted: 04/14/2024] [Indexed: 04/19/2024]
Abstract
The aim of this study was to investigate the expression and function of the transient receptor potential vanilloid 1 (TRPV1) in glioma. We found that the expression of TRPV1 mRNA and protein were upregulated in glioma compared with normal brain by qPCR and western blot analysis. In order to investigate the function of TRPV1 in glioma, short hairpin RNA (shRNA) and the inhibitor of TRPV1 were used. In vitro, the activation of TRPV1 induced cell apoptosis with decreased migration capability and inhibited proliferation, which was abolished upon TRPV1 pharmacological inhibition and silencing. Mechanistically, TRPV1 modulated glioma proliferation through the protein kinase B (Akt) signaling pathway. More importantly, in immunodeficient (NOD-SCID) mouse xenograft models, tumor size was significantly increased when TRPV1 expression was disrupted by a shRNA knockdown approach in vivo. Altogether, our findings indicate that TRPV1 negatively controls glioma cell proliferation in an Akt-dependent manner, which suggests that targeting TRPV1 may be a potential therapeutic strategy for glioma.
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Affiliation(s)
- Jingjing Cheng
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Mengliu Zeng
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Biwen Peng
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Ping Li
- Department of Physiology, Hubei Provincial Key Laboratory of Developmentally Originated Disease, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
| | - Shiyu Zhao
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
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2
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Deng R, Yu S, Ruan X, Liu H, Zong G, Cheng P, Tao R, Chen W, Wang A, Zhao Y, Wei Z, Lu Y. Capsaicin orchestrates metastasis in gastric cancer via modulating expression of TRPV1 channels and driving gut microbiota disorder. Cell Commun Signal 2023; 21:364. [PMID: 38129926 PMCID: PMC10734064 DOI: 10.1186/s12964-023-01265-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 08/10/2023] [Indexed: 12/23/2023] Open
Abstract
The association between capsaicin, the major natural pungent compound of chili peppers, and gastric cancer progression has engendered conflicting findings. In this work, we sought to explore the character of a high capsaicin diet in gastric cancer metastasis and its possible mechanism. The impact of high capsaicin consumption on gastric cancer metastasis was investigated in vivo (xenograft mouse and zebrafish models) and in vitro (biochemical and molecular assays). It was demonstrated that high diet of capsaicin gave rise to accelerate tumor metastasis, which was partially mediated by elevating the expression of transient receptor potential vanilloid 1 (TRPV1) in gastric cancer cells. Importantly, we found that genetic depletion of TRPV1 could reduce gastric cancer metastasis by diminishing the motility of tumor cells in vitro, but acted poorly in xenograft mouse model. Considering the distribution of capsaicin in vivo, 16S rRNA sequencing and fecal microbiota transplantation (FMT) were used to appraise whether the gut microbiota involved in the high capsaicin diet induced metastasis. It was demonstrated that the level of Firmicutes and Clostridiales was expressively boosted following the high consumption of capsaicin. This microbial shift contributed to the increased peripheral 5-hydroxytryptamine (5-HT) levels, yielding the aggravated metastatic burden. Collectively, our findings highlighted the potential risk of high capsaicin diet in promoting gastric cancer metastasis by virtue of modulating TRPV1 expression and gut microbiota composition, indicating the importance of controlled consumption of chili peppers for patients with gastric cancer. Video Abstract.
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Affiliation(s)
- Rui Deng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Suyun Yu
- State Key Laboratory Cultivation Base for Traditional Chinese Medicine (TCM) Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xingqiu Ruan
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Red Cross Hospital of Yulin City, Yulin, 537000, China
| | - Huan Liu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Gangfan Zong
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Peng Cheng
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ruizhi Tao
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wenxing Chen
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- State Key Laboratory Cultivation Base for Traditional Chinese Medicine (TCM) Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Aiyun Wang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- State Key Laboratory Cultivation Base for Traditional Chinese Medicine (TCM) Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yang Zhao
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Zhonghong Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory Cultivation Base for Traditional Chinese Medicine (TCM) Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
| | - Yin Lu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- State Key Laboratory Cultivation Base for Traditional Chinese Medicine (TCM) Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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Kaur H, Sarmah D, Datta A, Borah A, Yavagal DR, Bhattacharya P. Stem cells alleviate OGD/R mediated stress response in PC12 cells following a co-culture: modulation of the apoptotic cascade through BDNF-TrkB signaling. Cell Stress Chaperones 2023; 28:1041-1051. [PMID: 36622548 PMCID: PMC10746664 DOI: 10.1007/s12192-022-01319-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 12/02/2022] [Accepted: 12/17/2022] [Indexed: 01/10/2023] Open
Abstract
Apoptosis mediated by endoplasmic reticulum (ER) stress plays a crucial role in several neurovascular disorders, including ischemia/reperfusion injury (I/R injury). Previous in vitro and in vivo studies have suggested that following I/R injury, ER stress is vital for mediating CCAT-enhancer-binding protein homologous protein (CHOP) and caspase-12-dependent apoptosis. However, its modulation in the presence of stem cells and the underlying mechanism of cytoprotection remains elusive. In vivo studies from our lab have reported that post-stroke endovascular administration of stem cells renders neuroprotection and regulates apoptosis mediated by ER stress. In the current study, a more robust in vitro validation has been undertaken to decipher the mechanism of stem cell-mediated cytoprotection. Results from our study have shown that oxygen-glucose deprivation/reoxygenation (OGD/R) potentiated ER stress and apoptosis in the pheochromocytoma 12 (PC12) cell line as evident by the increase of protein kinase R (PKR)-like ER kinase (p-PERK), p-Eukaryotic initiation factor 2α subunit (EIF2α), activation transcription factor 4 (ATF4), CHOP, and caspase 12 expressions. Following the co-culture of PC12 cells with MSCs, ER stress was significantly reduced, possibly via modulating the brain-derived neurotrophic factor (BDNF) signaling. Furthermore, inhibition of BDNF by inhibitor K252a abolished the protective effects of BDNF secreted by MSCs following OGD/R. Our study suggests that inhibition of ER stress-associated apoptotic pathway with MSCs co-culture following OGD/R may help to alleviate cellular injury and further substantiate the use of stem cells as a therapeutic modality toward neuroprotection following hypoxic injury or stroke in clinical settings.
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Affiliation(s)
- Harpreet Kaur
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Deepaneeta Sarmah
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Aishika Datta
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India
| | - Anupom Borah
- Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, 788011, Assam, India
| | - Dileep R Yavagal
- Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, 33136, USA
| | - Pallab Bhattacharya
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, 382355, India.
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Frederico MJS, Cipriani A, Heim JBA, Mendes AKB, Aragón M, Gaspar JM, De Alencar NMN, Silva FRMB. Electrophilic Agonists Modulate the Transient Receptor Potential Ankyrin-1 Channels Mediated by Insulin and Glucagon-like Peptide-1 Secretion for Glucose Homeostasis. Pharmaceuticals (Basel) 2023; 16:1167. [PMID: 37631083 PMCID: PMC10458466 DOI: 10.3390/ph16081167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/07/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
This pre-clinical study investigated the transient receptor potential ankyrin-1 (TRPA1) channels on modulating targets for glucose homeostasis using agonists: the electrophilic agonists, cinnamaldehyde (CIN) and allyl isothiocyanate (AITC), and the non-electrophilic agonist, carvacrol (CRV). A glucose tolerance test was performed on rats. CIN and AITC (5, 10 and 20 mg/kg) or CRV (25, 100, 300, and 600 mg/kg) were administered intraperitoneally (i.p.), and glycemia was measured. In the intestine, Glucagon-like peptide-1 (GLP-1) and disaccharidase activity were evaluated (in vivo and in vitro, respectively). Furthermore, in vivo and in vitro insulin secretion was determined. Islets were used to measure insulin secretion and calcium influx. CIN and AITC improved glucose tolerance and increased insulin secretion in vivo and in vitro. CRV was unable to reduce glycemia. Electrophilic agonists, CIN and AITC, inhibited disaccharidases and acted as secretagogues in the intestine by inducing GLP-1 release in vivo and in vitro and contributed to insulin secretion and glycemia. The effect of CIN on calcium influx in pancreatic islets (insulin secretion) involves voltage-dependent calcium channels and calcium from stores. TRPA1 triggers calcium influx and potentiates intracellular calcium release to induce insulin secretion, suggesting that electrophilic agonists mediate this signaling transduction for the control of glycemia.
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Affiliation(s)
- Marisa Jadna Silva Frederico
- Laboratory of Hormones & Signal Transduction, Departament of Biochemistry, Center of Biological Sciences, Campus Trindade, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil; (A.C.); (J.B.A.H.); (A.K.B.M.); (J.M.G.)
- Laboratory of Biochemistry and Pharmacology, Departament of Pharmacology and Physiology, Drug Research and Development Center (DRDC), Medical School, Federal University of Ceará, Rua Coronel Nunes de Melo, Fortaleza 60430-275, CE, Brazil;
| | - Andreza Cipriani
- Laboratory of Hormones & Signal Transduction, Departament of Biochemistry, Center of Biological Sciences, Campus Trindade, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil; (A.C.); (J.B.A.H.); (A.K.B.M.); (J.M.G.)
| | - Jocelyn Brice Alexandre Heim
- Laboratory of Hormones & Signal Transduction, Departament of Biochemistry, Center of Biological Sciences, Campus Trindade, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil; (A.C.); (J.B.A.H.); (A.K.B.M.); (J.M.G.)
| | - Ana Karla Bittencourt Mendes
- Laboratory of Hormones & Signal Transduction, Departament of Biochemistry, Center of Biological Sciences, Campus Trindade, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil; (A.C.); (J.B.A.H.); (A.K.B.M.); (J.M.G.)
| | - Marcela Aragón
- Departament of Pharmacy, Science School, National University of Colombia, Bogotá 11011, Colombia;
| | - Joana Margarida Gaspar
- Laboratory of Hormones & Signal Transduction, Departament of Biochemistry, Center of Biological Sciences, Campus Trindade, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil; (A.C.); (J.B.A.H.); (A.K.B.M.); (J.M.G.)
| | - Nylane Maria Nunes De Alencar
- Laboratory of Biochemistry and Pharmacology, Departament of Pharmacology and Physiology, Drug Research and Development Center (DRDC), Medical School, Federal University of Ceará, Rua Coronel Nunes de Melo, Fortaleza 60430-275, CE, Brazil;
| | - Fátima Regina Mena Barreto Silva
- Laboratory of Hormones & Signal Transduction, Departament of Biochemistry, Center of Biological Sciences, Campus Trindade, Federal University of Santa Catarina, Florianópolis 88040-900, SC, Brazil; (A.C.); (J.B.A.H.); (A.K.B.M.); (J.M.G.)
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5
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Oz M, Lorke DE, Howarth FC. Transient receptor potential vanilloid 1 (TRPV1)-independent actions of capsaicin on cellular excitability and ion transport. Med Res Rev 2023. [PMID: 36916676 DOI: 10.1002/med.21945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 01/17/2023] [Accepted: 02/26/2023] [Indexed: 03/15/2023]
Abstract
Capsaicin is a naturally occurring alkaloid derived from chili pepper that is responsible for its hot pungent taste. Capsaicin is known to exert multiple pharmacological actions, including analgesia, anticancer, anti-inflammatory, antiobesity, and antioxidant effects. The transient receptor potential vanilloid subfamily member 1 (TRPV1) is the main receptor mediating the majority of the capsaicin effects. However, numerous studies suggest that the TRPV1 receptor is not the only target for capsaicin. An increasing number of studies indicates that capsaicin, at low to mid µM ranges, not only indirectly through TRPV1-mediated Ca2+ increases, but also directly modulates the functions of voltage-gated Na+ , K+ , and Ca2+ channels, as well as ligand-gated ion channels and other ion transporters and enzymes involved in cellular excitability. These TRPV1-independent effects are mediated by alterations of the biophysical properties of the lipid membrane and subsequent modulation of the functional properties of ion channels and by direct binding of capsaicin to the channels. The present study, for the first time, systematically categorizes this diverse range of non-TRPV1 targets and discusses cellular and molecular mechanisms mediating TRPV1-independent effects of capsaicin in excitable, as well as nonexcitable cells.
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Affiliation(s)
- Murat Oz
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Safat, Kuwait
| | - Dietrich E Lorke
- Department of Anatomy and Cellular Biology, College of Medicine and Health Sciences, Khalifa University, Abu Dhabi, United Arab Emirates.,Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Frank C Howarth
- Department of Physiology, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates
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6
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Deng Q, Ding K, Li Y, Jiao Y, Hu R, Zhang T, Wang Z, Tang BZ. Referential modification strategy based on phenolic hydroxyl-containing KSA luminogens for ER-targeting probe construction. Biomaterials 2022; 289:121767. [PMID: 36099711 DOI: 10.1016/j.biomaterials.2022.121767] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 08/18/2022] [Accepted: 08/25/2022] [Indexed: 11/02/2022]
Abstract
The endoplasmic reticulum (ER) plays essential roles in various physiological processes and is intimately connected to kinds of diseases. The development of ER-targeting theranostic agents is highly demanded for precise treatments, however, the effective and referential strategies for the construction of ER-targeting probes are limited. Herein, we developed series of ER-targeting luminogens based on keto-salicylaldehyde azine (KSA) framework by introducing phenolic hydroxyl group, which present good theranostic performance with selective enrichment in ER. Under systematical structure modulation, the key role of phenolic hydroxyl group at K-terminal in ER-targeting was experimentally confirmed. Besides, the cyanobenzyl moiety at S-terminal can enhance the luminous efficiency and improve cellular uptake ability. Moreover, the generated reactive oxygen species (ROS) of these KSA derivatives can efficiently trigger ER stress to induce the apoptosis of cancer cells, resulting in the effective inhibition of tumor cells both in vitro and in vivo. Therefore, this feasible modification strategy of inserting phenolic hydroxyl group to common multi-aryl-based luminogens provides a reliable and referential approach for ER-targeting probe establishment.
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Affiliation(s)
- Qiyun Deng
- Center for Aggregation-Induced Emission, AIE Institute, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, Center for Aggregation-Induced Emission, South China University of Technology, Guangzhou, 510640, PR China
| | - Keke Ding
- Department of Urology, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), No. 2 Zheshan Road, Wuhu, 241001, PR China; Department of Urology, The First Affiliated Hospital of Soochow University, NO. 188 Shizi Road, Suzhou, 215006, PR China
| | - Yin Li
- Center for Aggregation-Induced Emission, AIE Institute, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, Center for Aggregation-Induced Emission, South China University of Technology, Guangzhou, 510640, PR China
| | - Yawen Jiao
- School of Chemistry and Chemical Engineering, Shandong University of Technology, Zibo, 255049, PR China
| | - Rong Hu
- Center for Aggregation-Induced Emission, AIE Institute, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, Center for Aggregation-Induced Emission, South China University of Technology, Guangzhou, 510640, PR China; School of Chemistry and Chemical Engineering, University of South China, Hengyang, 421001, PR China.
| | - Tian Zhang
- School of Chemistry and Chemical Engineering, Shandong University of Technology, Zibo, 255049, PR China.
| | - Zhiming Wang
- Center for Aggregation-Induced Emission, AIE Institute, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, Center for Aggregation-Induced Emission, South China University of Technology, Guangzhou, 510640, PR China.
| | - Ben Zhong Tang
- Center for Aggregation-Induced Emission, AIE Institute, State Key Laboratory of Luminescent Materials and Devices, Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates, Center for Aggregation-Induced Emission, South China University of Technology, Guangzhou, 510640, PR China; School of Science and Engineering, Shenzhen Institute of Aggregate Science and Technology, The Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, PR China
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Anticancer Activity of Natural and Semi-Synthetic Drimane and Coloratane Sesquiterpenoids. Molecules 2022; 27:molecules27082501. [PMID: 35458699 PMCID: PMC9031474 DOI: 10.3390/molecules27082501] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 12/12/2022] Open
Abstract
Drimane and coloratane sesquiterpenoids are present in several plants, microorganisms, and marine life. Because of their cytotoxic activity, these sesquiterpenoids have received increasing attention as a source for new anticancer drugs and pharmacophores. Natural drimanes and coloratanes, as well as their semi-synthetic derivatives, showed promising results against cancer cell lines with in vitro activities in the low micro- and nanomolar range. Despite their high potential as novel anticancer agents, the mode of action and structure–activity relationships of drimanes and coloratanes have not been completely enlightened nor systematically reviewed. Our review aims to give an overview of known structures and derivatizations of this class of sesquiterpenoids, as well as their activity against cancer cells and potential modes-of-action. The cytotoxic activities of about 40 natural and 25 semi-synthetic drimanes and coloratanes are discussed. In addition to that, we give a summary about the clinical significance of drimane and coloratane sesquiterpenoids.
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8
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Zhai K, Liskova A, Kubatka P, Büsselberg D. Calcium Entry through TRPV1: A Potential Target for the Regulation of Proliferation and Apoptosis in Cancerous and Healthy Cells. Int J Mol Sci 2020; 21:E4177. [PMID: 32545311 PMCID: PMC7312732 DOI: 10.3390/ijms21114177] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
Intracellular calcium (Ca2+) concentration ([Ca2+]i) is a key determinant of cell fate and is implicated in carcinogenesis. Membrane ion channels are structures through which ions enter or exit the cell, depending on the driving forces. The opening of transient receptor potential vanilloid 1 (TRPV1) ligand-gated ion channels facilitates transmembrane Ca2+ and Na+ entry, which modifies the delicate balance between apoptotic and proliferative signaling pathways. Proliferation is upregulated through two mechanisms: (1) ATP binding to the G-protein-coupled receptor P2Y2, commencing a kinase signaling cascade that activates the serine-threonine kinase Akt, and (2) the transactivation of the epidermal growth factor receptor (EGFR), leading to a series of protein signals that activate the extracellular signal-regulated kinases (ERK) 1/2. The TRPV1-apoptosis pathway involves Ca2+ influx and efflux between the cytosol, mitochondria, and endoplasmic reticulum (ER), the release of apoptosis-inducing factor (AIF) and cytochrome c from the mitochondria, caspase activation, and DNA fragmentation and condensation. While proliferative mechanisms are typically upregulated in cancerous tissues, shifting the balance to favor apoptosis could support anti-cancer therapies. TRPV1, through [Ca2+]i signaling, influences cancer cell fate; therefore, the modulation of the TRPV1-enforced proliferation-apoptosis balance is a promising avenue in developing anti-cancer therapies and overcoming cancer drug resistance. As such, this review characterizes and evaluates the role of TRPV1 in cell death and survival, in the interest of identifying mechanistic targets for drug discovery.
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Affiliation(s)
- Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, PO Box 24144, Qatar;
| | - Alena Liskova
- Clinic of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia;
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, PO Box 24144, Qatar;
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9
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Huang R, Wang F, Yang Y, Ma W, Lin Z, Cheng N, Long Y, Deng S, Li Z. Recurrent activations of transient receptor potential vanilloid-1 and vanilloid-4 promote cellular proliferation and migration in esophageal squamous cell carcinoma cells. FEBS Open Bio 2019; 9:206-225. [PMID: 30761248 PMCID: PMC6356177 DOI: 10.1002/2211-5463.12570] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 06/19/2018] [Accepted: 10/23/2018] [Indexed: 12/27/2022] Open
Abstract
Some members of the transient receptor potential vanilloid (TRPV) subfamily of cation channels are thermosensitive. Earlier studies have revealed the distribution and functions of these thermo‐TRPVs (TRPV1–4) in various organs, but their expression and function in the human esophagus are not fully understood. Here, we probed for the expression of the thermo‐TRPVs in one nontumor human esophageal squamous cell line and two esophageal squamous cell carcinoma (ESCC) cell lines. TRPV1, TRPV2, and TRPV4 proteins were found to be upregulated in ESCC cells, while TRPV3 was not detectable in any of these cell lines. Subsequently, channel function was evaluated via monitoring of Ca2+ transients by Ca2+ imaging and nonselective cation channel currents were recorded by whole‐cell patch clamp. We found that TRPV4 was activated by heat at 28 °C–35 °C, whereas TRPV1 and TRPV2 were activated by higher, noxious temperatures (44 °C and 53 °C, respectively). Furthermore, TRPV1 was activated by capsaicin (EC50 = 20.32 μm), and this effect was antagonized by AMG9810; TRPV2 was activated by a newly developed cannabinoid compound, O1821, and inhibited by tranilast. In addition, TRPV4 was activated by hypotonic solutions (220 m Osm), and this effect was abolished by ruthenium red. The effects of TRPV1 and TRPV4 on ESCC were also explored. Our data, for the first time, showed that the overactivation of TRPV1 and TRPV4 promoted the proliferation and/or migration of ESCC cells. In summary, TRPV1, TRPV2, and TRPV4 were functionally expressed in human esophageal squamous cells, and thermo‐TRPVs might play an important role in the development of ESCC.
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Affiliation(s)
- Rongqi Huang
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China.,University of Chinese Academy of Sciences Beijing China
| | - Fei Wang
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China
| | - Yuchen Yang
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China
| | - Wenbo Ma
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China
| | - Zuoxian Lin
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China
| | - Na Cheng
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China.,Department of Anatomy and Neurobiology Xiangya School of Medicine Central South University Changsha China
| | - Yan Long
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China
| | - Sihao Deng
- Department of Anatomy and Neurobiology Xiangya School of Medicine Central South University Changsha China
| | - Zhiyuan Li
- Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou China.,University of Chinese Academy of Sciences Beijing China.,Department of Anatomy and Neurobiology Xiangya School of Medicine Central South University Changsha China.,GZMU-GIBH Joint School of Life Sciences Guangzhou Medical University China
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Supra-pharmacological concentration of capsaicin stimulates brown adipogenesis through induction of endoplasmic reticulum stress. Sci Rep 2018; 8:845. [PMID: 29339762 PMCID: PMC5770457 DOI: 10.1038/s41598-018-19223-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 12/18/2017] [Indexed: 01/12/2023] Open
Abstract
We previously showed that brown (pre)adipocytes express Trpv1, a capsaicin receptor, and that capsaicin stimulates differentiation of brown preadipocytes in the late stages of brown adipogenesis. The present study revealed that treatment with 100 μM capsaicin stimulates brown adipogenesis by inducing endoplasmic reticulum (ER) stress. Treatment with capsaicin (100 μM) during brown adipogenesis enhanced lipid accumulation and the expression of Ucp1, a gene selectively expressed in brown adipocytes. Capsaicin treatment also caused an increase in the cytosolic calcium concentration even when extracellular calcium was removed. I-RTX, a Trpv1 inhibitor, did not modulate the increase in cytosolic calcium concentration, lipid accumulation or Ucp1 expression. Previous studies revealed that the release of calcium from the ER induces ER stress, leading to the conversion of X-box binding protein 1 (Xbp1) pre-mRNA to spliced Xbp1 (sXbp1) as well as the up-regulation of Chop expression. Capsaicin treatment increased the expression of sXbp1 and Chop in brown preadipocytes and did not enhance lipid accumulation or Ucp1 expression in Xbp1 knockdown cells. The present results describe a novel mechanism of brown adipogenesis regulation via ER stress that is induced by a supra-pharmacological concentration of capsaicin.
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Lekes D, Szadvari I, Krizanova O, Lopusna K, Rezuchova I, Novakova M, Novakova Z, Parak T, Babula P. Nilotinib induces ER stress and cell death in H9c2 cells. Physiol Res 2017; 65:S505-S514. [PMID: 28006933 DOI: 10.33549/physiolres.933504] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Tyrosine kinases inhibitors (TKi) represent a relatively novel class of anticancer drugs that target cellular pathways overexpressed in certain types of malignancies, such as chronic myeloid leukaemia (CML). Nilotinib, ponatinib and imatinib exhibit cardiotoxic and vascular effects. In this study, we focused on possible cardiotoxicity of nilotinib using H9c2 cells as a suitable cell model. We studied role of endoplasmic reticulum (ER) stress and apoptosis in nilotinib toxicity using a complex approach. Nilotinib impaired mitochondrial function and induced formation of ROS under clinically relevant concentrations. In addition, ability of nilotinib to induce ER stress has been shown. These events result in apoptotic cell death. All these mechanisms contribute to cytotoxic effect of the drug. In addition, involvement of ER stress in nilotinib toxicity may be important in co-treatment with pharmaceuticals affecting ER and ER stress, e.g. beta-blockers or sartans, and should be further investigated.
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Affiliation(s)
- D Lekes
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
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12
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Pedotti S, Patti A, Dedola S, Barberis A, Fabbri D, Dettori MA, Serra PA, Delogu G. Synthesis of new ferrocenyl dehydrozingerone derivatives and their effects on viability of PC12 cells. Polyhedron 2016. [DOI: 10.1016/j.poly.2016.05.039] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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13
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Li F, Zheng X, Liu Y, Li P, Liu X, Ye F, Zhao T, Wu Q, Jin X, Li Q. Different Roles of CHOP and JNK in Mediating Radiation-Induced Autophagy and Apoptosis in Breast Cancer Cells. Radiat Res 2016; 185:539-48. [PMID: 27135967 DOI: 10.1667/rr14344.1] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Unfolded protein response (UPR) is comprised of complex and conserved stress pathways that function as a short-term adaptive mechanism to reduce levels of unfolded or misfolded proteins and maintain homeostasis in the endoplasmic reticulum (ER). UPR can be triggered by prolonged or persistent ER stress under many physiological or pathological conditions, including radiation exposure. Radiation-induced ER stress elicits autophagy and apoptosis in cancer cells, where C/EBP homologous protein (CHOP) and c-Jun NH2-terminal kinase (JNK) may play crucial roles. However, the specific mechanisms that regulate autophagy and apoptosis through CHOP and JNK after radiation exposure and how the balance of these activities determines the cellular radiosensitivity remain largely unclear. In this study, we found that exposure to X-ray radiation induced ER stress, UPR and high expression of CHOP and JNK. Furthermore, autophagy and apoptosis occurred in sequential order when breast cancer MDA-MB-231 and MCF-7 cells were exposed to X-ray radiation. CHOP gene knockdown with RNA interference inhibited autophagy and enhanced radiosensitivity in MDA-MB-231 cells, while impacting apoptosis and subsequently increasing radioresistance in MCF-7 cells. However, treatment with JNK inhibitor decreased autophagy while promoting apoptosis, thereby leading to radiosensitivity in both cell lines. Our results indicate that CHOP mediates radiation-induced autophagy and apoptosis in a cellular environment. Importantly, the functional consistency of regulating apoptosis and autophagy in these two irradiated breast cancer cell lines suggests that JNK may be more useful as a potential target for maximizing the efficacy of radiation therapy for breast cancers.
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Affiliation(s)
- Feifei Li
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and.,d University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaogang Zheng
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and.,d University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yan Liu
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and.,d University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ping Li
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
| | - Xiongxiong Liu
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
| | - Fei Ye
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and.,d University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ting Zhao
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
| | - Qingfeng Wu
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China
| | - Xiaodong Jin
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
| | - Qiang Li
- a Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China;,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou 730000, China;,c Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China; and
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14
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Han SS, Han S, Kamberos NL. Piperlongumine inhibits the proliferation and survival of B-cell acute lymphoblastic leukemia cell lines irrespective of glucocorticoid resistance. Biochem Biophys Res Commun 2014; 452:669-75. [PMID: 25193702 DOI: 10.1016/j.bbrc.2014.08.131] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 08/25/2014] [Indexed: 01/10/2023]
Abstract
Piperlongumine (PL), a pepper plant alkaloid from Piper longum, has anti-inflammatory and anti-cancer properties. PL selectively kills both solid and hematologic cancer cells, but not normal counterparts. Here we evaluated the effect of PL on the proliferation and survival of B-cell acute lymphoblastic leukemia (B-ALL), including glucocorticoid (GC)-resistant B-ALL. Regardless of GC-resistance, PL inhibited the proliferation of all B-ALL cell lines, but not normal B cells, in a dose- and time-dependent manner and induced apoptosis via elevation of ROS. Interestingly, PL did not sensitize most of B-ALL cell lines to dexamethasone (DEX). Only UoC-B1 exhibited a weak synergistic effect between PL and DEX. All B-ALL cell lines tested exhibited constitutive activation of multiple transcription factors (TFs), including AP-1, MYC, NF-κB, SP1, STAT1, STAT3, STAT6 and YY1. Treatment of the B-ALL cells with PL significantly downregulated these TFs and modulated their target genes. While activation of AURKB, BIRC5, E2F1, and MYB mRNA levels were significantly downregulated by PL, but SOX4 and XBP levels were increased by PL. Intriguingly, PL also increased the expression of p21 in B-ALL cells through a p53-independent mechanism. Given that these TFs and their target genes play critical roles in a variety of hematological malignancies, our findings provide a strong preclinical rationale for considering PL as a new therapeutic agent for the treatment of B-cell malignancies, including B-ALL and GC-resistant B-ALL.
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Affiliation(s)
- Seong-Su Han
- Division of Pediatric Hematology-Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
| | - Sangwoo Han
- Health and Human Physiology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Natalie L Kamberos
- Division of Pediatric Hematology-Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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