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Wang G, Liu D, Leng J, Jin D, Wang Q, Wang H, Bu Y, Wang F, Hui Y. TMCO1 regulates energy metabolism and mitochondrial function of hepatocellular carcinoma cells through TOMM20, affecting the growth of subcutaneous graft tumors and infiltration of CAFs. Biochem Cell Biol 2025; 103:1-15. [PMID: 39566034 DOI: 10.1139/bcb-2024-0091] [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] [Indexed: 11/22/2024] Open
Abstract
This study mainly shows the role of endoplasmic reticulum transmembrane and coiled coil domains 1 (TMCO1) in the regulatory mechanism of hepatocellular carcinoma (HCC). Invasion and migration capacity were detected by Transwell and wound healing after TMCO1 and TOMM20 overexpression and knockdown, and mitochondrial function was detected through reactive oxygen species (ROS), mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (MMP), and ATP production. A model of subcutaneous tumor formation in nude mice was established to detect the effect of TMCO1 on tumor formation. The results showed that overexpression of TMCO1 significantly promoted HCC cell metastasis, promoted cell proliferation and ATP production, inhibited cell apoptosis, mPTP opening and ROS production, mediated the increase of MMP level and cytoskeletal remodeling. However, knocking down TMCO1 can have the opposite effect. More importantly, knocking down TOMM20 can block the regulation effect of TMCO1, and TOMM20 overexpression can alleviate the inhibitory effect of knocking down TMCO1 on the development of liver cancer cells. In animal models, knockdown of TMCO1 expression significantly inhibited the growth of subcutaneous implant tumors. This suggests that TMCO1 may be a potential and valuable therapeutic target for liver cancer.
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Affiliation(s)
- Genwang Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Di Liu
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Junzhi Leng
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Dong Jin
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Qi Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Hao Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Yang Bu
- Department of Hepatobiliary Surgery, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan 750002, Ningxia, China
| | - Feng Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
| | - Yongfeng Hui
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia, China
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Liao Y, Cheng W, Mou R, Li X, Jia Y. RGN as a prognostic biomarker with immune infiltration and ceRNA in lung squamous cell carcinoma. Sci Rep 2023; 13:7553. [PMID: 37161020 PMCID: PMC10170118 DOI: 10.1038/s41598-023-32217-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/24/2023] [Indexed: 05/11/2023] Open
Abstract
Regucalcin (RGN) is a potent inhibitory protein of calcium signaling and expresses in various tissues. However, the role of RGN in the tumor immunological microenvironment in lung squamous cell carcinoma (LUSC) remains unclear. This study identified the expression of RGN from public databases and immunohistochemistry with clinical specimen. The association between RGN and the tumor immune microenvironment (TIME) was investigated in LUSC by ESTIMATE and CIBERSORT algorithms. Similarly, the Tumor IMmune Estimation Resource (TIMER) database was used to identify the correlation between RGN and immune cells. The ceRNA network was established based on the data obtained from public databases. Finally, prediction of drug response to chemotherapy and immunotherapy was performed to evaluate clinical significance. This study found that RGN expression was significantly downregulated in tumor tissues and closely related to clinical factors and prognosis of LUSC patients. Differentially expressed genes (DEGs) grouped by the expression of RGN were mostly involved in immunobiological processes such as humoral immune response and leukocyte mediated immunity. RGN and its related miRNA (has-miR-203a-3p) and lncRNAs (ZNF876P and PSMG3-AS1) constructed the novel prognosis-related ceRNA network. Plasma cells, T cells CD4 memory resting, Macrophages M0, Macrophages M1, Mast cells resting, Mast cells activated and Neutrophils showed significantly different levels of infiltration between high and low RGN expression groups. The TIMER database showed that RGN expression was positively correlated with certain immune infiltrating cells. High RGN expression group showed a higher TIDE score, a higher dysfunction score and a lower MSI score, presenting a possible lower efficacy after accepting the immunotherapy than low RGN expression group. RGN expression was closely associated with prognosis of LUSC patients and played an important role in tumor microenvironment. This suggests that RGN could be a promising biomarker for assessing immunotherapy efficacy and prognosis.
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Affiliation(s)
- Yang Liao
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300008, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300008, China
| | - Wen Cheng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300008, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300008, China
| | - Ruiyu Mou
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300008, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300008, China
| | - Xiaojiang Li
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300008, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300008, China.
| | - Yingjie Jia
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300008, China.
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, 300008, China.
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Krause W. Resistance to prostate cancer treatments. IUBMB Life 2022; 75:390-410. [PMID: 35978491 DOI: 10.1002/iub.2665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/09/2022] [Indexed: 12/14/2022]
Abstract
A review of the current treatment options for prostate cancer and the formation of resistance to these regimens has been compiled including primary, acquired, and cross-resistance. The diversification of the pathways involved and the escape routes the tumor is utilizing have been addressed. Whereas early stages of tumor can be cured, there is no treatment available after a point of no return has been reached, leaving palliative treatment as the only option. The major reasons for this outcome are the heterogeneity of tumors, both inter- and intra-individually and the nearly endless number of escape routes, which the tumor can select to overcome the effects of treatment. This means that more focus should be applied to the individualization of both diagnosis and therapy of prostate cancer. In addition to current treatment options, novel drugs and ongoing clinical trials have been addressed in this review.
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Tülüce Y, Hussein AI, Koyuncu İ, Kiliç A, Durgun M. The effect of a bis-structured Schiff base on apoptosis, cytotoxicity, and DNA damage of breast cancer cells. J Biochem Mol Toxicol 2022; 36:e23148. [PMID: 35719061 DOI: 10.1002/jbt.23148] [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: 10/25/2021] [Revised: 05/09/2022] [Accepted: 06/06/2022] [Indexed: 11/09/2022]
Abstract
Developing new anticancer agents are crucial for cancer treatment. Antiproliferative activity of L1H as a bis-structured Schiff base was subjected to preliminary research in eight different kinds of cell lines by the cell viability method using different concentrations to determine their inhibitory concentration. L1H demonstrated the highest cytotoxicity in human breast cancer cell line MCF-7. In this perspective, the MCF-7 cell line was cultured for the examination of different molecular techniques, including MTT, apoptosis analysis by enzyme-linked immunosorbent assay (ELISA), and comet assay. Moreover, the DNA ladder, acridine orange/ethidium bromide as another apoptotic cell analysis, markers of oxidative stress, and total antioxidant status, total thiol, and GSH as nonenzymatic antioxidants assay were conducted. The above techniques have proven that L1H is a growth inhibitor effect when compared to cisplatin as a positive control in human breast cancer cells, especially those affected by L1H. The findings clearly show that L1H evaluated in MCF-7 cell lines causes rising or induced apoptosis, DNA damage, diminished antioxidant status against the increase of oxidized protein, and prevents cell proliferation. Manifold evidence supported our hypothesis that L1H has a potential therapeutically improved effect against the MCF-7 cell line, and then without a doubt is a suitable candidate drug for investigating cancers next.
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Affiliation(s)
- Yasin Tülüce
- Department of Medical Biology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Türkiye
| | - Azhee Ibrahim Hussein
- Department of Medical Biology, Health Science Institute, Van Yuzuncu Yil University, Van, Türkiye
| | - İsmail Koyuncu
- Department of Biochemistry, Faculty of Medicine, Harran University, Sanliurfa, Türkiye
| | - Ahmet Kiliç
- Department of Chemistry, Faculty of Science and Art, Harran University, Sanliurfa, Türkiye
| | - Mustafa Durgun
- Department of Chemistry, Faculty of Science and Art, Harran University, Sanliurfa, Türkiye
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Yamaguchi M, Murata T, Ramos JW. Overexpression of regucalcin blocks the migration, invasion, and bone metastatic activity of human prostate cancer cells: Crosstalk between cancer cells and bone cells. Prostate 2022; 82:1025-1039. [PMID: 35365850 DOI: 10.1002/pros.24348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/11/2021] [Accepted: 01/03/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Prostate cancer is a bone metastatic cancer and is the second leading cause of cancer-related death in men. Prolonged progression-free survival of prostate cancer patients is associated with high regucalcin expression in the tumor tissues. This study investigates the underlying mechanism by which regucalcin prevents bone metastatic activity of prostate cancer cells. METHODS Human prostate cancer PC-3 or DU-145 wild-type cells or regucalcin-overexpressing PC-3 or DU-145 cells (transfectants) were cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum. RESULTS Overexpressed regucalcin suppressed the migration and invasion of bone metastatic human prostate cancer cells in vitro, and it reduced the levels of key proteins in metastasis including Ras, Akt, MAPK, RSK-2, mTOR, caveolin-1, and integrin β1. Invasion of prostate cancer cells was promoted by coculturing with preosteoblastic MC3T3-E1 or preosteoclastic RAW264.7 cells. Coculturing with cancer cells and bone cells repressed the growth of preosteoblastic cells and enhanced osteoclastogenesis of preosteoclastic cells, and these alterations were caused by a conditioned medium from cancer cell culture. Disordered differentiation of bone cells was prevented by regucalcin overexpression. Production of tumor necrosis factor-α (TNF-α) in cancer cells was blocked by overexpressed regucalcin. Of note, the effects of conditioned medium on bone cells were prevented by NF-κB inhibitor. TNF-α may be important as a mediator in the crosstalk between cancer cells and bone cells. CONCLUSION Overexpression of regucalcin suppressed the migration, invasion, and bone metastatic activity of human prostate cancer cells. This study may provide a new strategy for therapy with the regucalcin gene transfer.
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Affiliation(s)
- Masayoshi Yamaguchi
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Hawaii, USA
| | - Tomiyasu Murata
- Laboratory of Molecular Biology, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Joe W Ramos
- Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Hawaii, USA
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Effects of 6-Month Square Stepping Exercise Intervention on Physical and Cognitive Competence, Regucalcin, and Body Composition in Older People: Study Protocol for a Randomised Control Trial. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19053086. [PMID: 35270778 PMCID: PMC8910098 DOI: 10.3390/ijerph19053086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/10/2022] [Accepted: 03/02/2022] [Indexed: 11/17/2022]
Abstract
Background: Age-related changes negatively affect physical fitness, body composition, and executive function and produce a decrease in regucalcin level expression in blood. The square-stepping exercise (SSE) is a balance and lower-limb strength training programme used to prevent falls and stimulate cognitive function in older adults. This project aims to analyse the effects of SSE on executive function, regucalcin expression, fall prevention, body composition, and physical fitness in people over 65 years old. Methods: A randomized controlled trial will be conducted. A total of 90 older people over 65 years old will be recruited and randomly assigned to 2 groups: experimental (n = 45) and control (n = 45). The experimental group will perform an SSE-based intervention for 6 months (2 times per week), while the control group do not follow any treatment. Results: The main outcome will be balance, but other motor (body mass index, upper- and lower-limb strength, flexibility, and speed-agility) and cognitive variables (executive functions and attention) will be assessed. The expression of regucalcin levels will also be evaluated. Therefore, this project aims to analyse the effect of a 6-month SSE intervention on cognitive and motor competence, physical fitness, regucalcin levels, fall risk, and body composition in older people. If the intervention proves to be effective, it could be implemented in centres, entities, and associations specialized in elderly care.
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Enzymatically Crosslinked In Situ Synthesized Silk/Gelatin/Calcium Phosphate Hydrogels for Drug Delivery. MATERIALS 2021; 14:ma14237191. [PMID: 34885345 PMCID: PMC8658330 DOI: 10.3390/ma14237191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 11/15/2021] [Accepted: 11/22/2021] [Indexed: 11/17/2022]
Abstract
Our research focuses on combining the valuable properties of silk fibroin (SF) and calcium phosphate (CaP). SF is a natural protein with an easily modifiable structure; CaP is a mineral found in the human body. Most of the new age biocomposites lack interaction between organic/inorganic phase, thus SF/CaP composite could not only mimic the natural bone, but could also be used to make drug delivery systems as well, which can ensure both healing and regeneration. CaP was synthesized in situ in SF at different pH values, and then crosslinked with gelatin (G), horseradish peroxide (HRP), and hydrogen peroxide (H2O2). In addition, dexamethasone phosphate (DEX) was incorporated in the hydrogel and drug delivery kinetics was studied. Hydrogel made at pH 10.0 was found to have the highest gel fraction 110.24%, swelling degree 956.32%, and sustained drug delivery for 72 h. The highest cell viability was observed for the hydrogel, which contained brushite (pH 6)-512.43%.
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8
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Bai B, Chen Q, Jing R, He X, Wang H, Ban Y, Ye Q, Xu W, Zheng C. Molecular Basis of Prostate Cancer and Natural Products as Potential Chemotherapeutic and Chemopreventive Agents. Front Pharmacol 2021; 12:738235. [PMID: 34630112 PMCID: PMC8495205 DOI: 10.3389/fphar.2021.738235] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
Prostate cancer is the second most common malignant cancer in males. It involves a complex process driven by diverse molecular pathways that closely related to the survival, apoptosis, metabolic and metastatic characteristics of aggressive cancer. Prostate cancer can be categorized into androgen dependent prostate cancer and castration-resistant prostate cancer and cure remains elusive due to the developed resistance of the disease. Natural compounds represent an extraordinary resource of structural scaffolds with high diversity that can offer promising chemical agents for making prostate cancer less devastating and curable. Herein, those natural compounds of different origins and structures with potential cytotoxicity and/or in vivo anti-tumor activities against prostate cancer are critically reviewed and summarized according to the cellular signaling pathways they interfere. Moreover, the anti-prostate cancer efficacy of many nutrients, medicinal plant extracts and Chinese medical formulations were presented, and the future prospects for the application of these compounds and extracts were discussed. Although the failure of conventional chemotherapy as well as involved serious side effects makes natural products ideal candidates for the treatment of prostate cancer, more investigations of preclinical and even clinical studies are necessary to make use of these medical substances reasonably. Therefore, the elucidation of structure-activity relationship and precise mechanism of action, identification of novel potential molecular targets, and optimization of drug combination are essential in natural medicine research and development.
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Affiliation(s)
- Bingke Bai
- Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Qianbo Chen
- Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Rui Jing
- Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Xuhui He
- Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Hongrui Wang
- Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Yanfei Ban
- Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Qi Ye
- Department of Biological Science, College of Life Science, Fujian Agriculture and Forestry University, Fuzhou, China
| | - Weiheng Xu
- Department of Biochemical Pharmacy, School of Pharmacy, Second Military Medical University, Shanghai, China
| | - Chengjian Zheng
- Department of Chinese Medicine Authentication, School of Pharmacy, Second Military Medical University, Shanghai, China
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Bergantin LB. Diabetes and inflammatory diseases: An overview from the perspective of Ca 2+/3'-5'-cyclic adenosine monophosphate signaling. World J Diabetes 2021; 12:767-779. [PMID: 34168726 PMCID: PMC8192245 DOI: 10.4239/wjd.v12.i6.767] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 12/29/2020] [Accepted: 03/08/2021] [Indexed: 02/06/2023] Open
Abstract
A large amount of evidence has supported a clinical link between diabetes and inflammatory diseases, e.g., cancer, dementia, and hypertension. In addition, it is also suggested that dysregulations related to Ca2+ signaling could link these diseases, in addition to 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways. Thus, revealing this interplay between diabetes and inflammatory diseases may provide novel insights into the pathogenesis of these diseases. Publications involving signaling pathways related to Ca2+ and cAMP, inflammation, diabetes, dementia, cancer, and hypertension (alone or combined) were collected by searching PubMed and EMBASE. Both signaling pathways, Ca2+ and cAMP signaling, control the release of neurotransmitters and hormones, in addition to neurodegeneration, and tumor growth. Furthermore, there is a clear relationship between Ca2+ signaling, e.g., increased Ca2+ signals, and inflammatory responses. cAMP also regulates pro- and anti-inflammatory responses. Due to the experience of our group in this field, this article discusses the role of Ca2+ and cAMP signaling in the correlation between diabetes and inflammatory diseases, including its pharmacological implications. As a novelty, this article also includes: (1) A timeline of the major events in Ca2+/cAMP signaling; and (2) As coronavirus disease 2019 (COVID-19) is an emerging and rapidly evolving situation, this article also discusses recent reports on the role of Ca2+ channel blockers for preventing Ca2+ signaling disruption due to COVID-19, including the correlation between COVID-19 and diabetes.
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10
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Bergantin LB. A Hypothesis for the Relationship between Depression and Cancer: Role of Ca2+/cAMP Signalling. Anticancer Agents Med Chem 2021; 20:777-782. [PMID: 32077833 DOI: 10.2174/1871520620666200220113817] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 10/02/2019] [Accepted: 01/14/2020] [Indexed: 01/17/2023]
Abstract
Limitations on the pharmacotherapy and a high prevalence worldwide are critical issues related to depression and cancer. It has been discussed that a dysregulation of intracellular Ca2+ homeostasis is involved in the pathogenesis of both these diseases. In addition, depression raises the risk of cancer incidence. Consistent data support the concept that depression is an independent risk issue for cancer. However, the cellular mechanisms involved in this link between depression and cancer remain uncertain. Considering our previous reports about Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling), I herein discussed the putative contribution of Ca2+/cAMP signalling in this link between depression and cancer. Moreover, it is important to take depression into account during the process of prevention and treatment of cancer.
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Affiliation(s)
- Leandro B Bergantin
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Rua Pedro de Toledo, 669, Vila Clementino, Sao Paulo, SP, Brazil
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Sharma S, Pei X, Xing F, Wu SY, Wu K, Tyagi A, Zhao D, Deshpande R, Ruiz MG, Singh R, Lyu F, Watabe K. Regucalcin promotes dormancy of prostate cancer. Oncogene 2021; 40:1012-1026. [PMID: 33323968 PMCID: PMC8958430 DOI: 10.1038/s41388-020-01565-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 11/04/2020] [Accepted: 11/11/2020] [Indexed: 02/08/2023]
Abstract
Prostate cancer is one of the leading causes of mortality in men. The major cause of death in prostate cancer patients can be attributed to metastatic spread of disease or tumor recurrence after initial treatment. Prostate tumors are known to remain undetected or dormant for a long period of time before they progress locoregionally or at distant sites as overt tumors. However, the molecular mechanism of dormancy is yet poorly understood. In this study, we performed a differential gene expression analysis and identified a gene, Regucalcin (RGN), which promotes dormancy of prostate cancer. We found that cancer patients expressing higher level of RGN showed significantly longer recurrence-free and overall- survival. Using a doxycycline-inducible RGN expression system, we showed that ectopic expression of RGN in prostate tumor cells induced dormancy in vivo, while following suppression of RGN triggered recurrence of tumor growth. On the other hand, silencing RGN in LNCap cells promoted its outgrowth in the tibia of mice. Importantly, RGN promoted multiple known hallmarks of tumor dormancy including activation of p38 MAPK, decrease in Erk signaling and inhibition of FOXM1 expression. Furthermore, we found that RGN significantly suppressed angiogenesis by increasing secretory miR-23c level in the exosomes. Intriguingly, FOXM1 was found to negatively regulate miR-23c expression in prostate cancer. In addition, we identified 11 RGN downstream target genes that independently predicted longer recurrence-free survival in patients. We found that expression of these genes was regulated by FOXM1 and/or p38 MAPK. These findings suggest a critical role of RGN in prostate cancer dormancy, and the utility of RGN signaling and exosomal miR-23c as biomarkers for predicting recurrence.
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Affiliation(s)
- Sambad Sharma
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Xinhong Pei
- Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Fei Xing
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Shih-Ying Wu
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Kerui Wu
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Abhishek Tyagi
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Dan Zhao
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Ravindra Deshpande
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Marco Gabriel Ruiz
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | | | - Feng Lyu
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Kounosuke Watabe
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
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Yang C, Wang Y, Bai JQ, Zhang JR, Hu PY, Zhu Y, Ouyang Q, Su HM, Li QY, Zhang P. Mechanism of transmembrane and coiled-coil domain 1 in the regulation of proliferation and migration of A549 cells. Oncol Lett 2020; 20:159. [PMID: 32934727 DOI: 10.3892/ol.2020.12020] [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: 08/26/2019] [Accepted: 06/29/2020] [Indexed: 11/05/2022] Open
Abstract
Bioinformatics analyses have shown that transmembrane and coiled-coil domain 1 (TMCO1) may be associated with lung adenocarcinoma. However, to the best of our knowledge, no current research has determined whether TMCO1 is involved in the development of lung adenocarcinoma. The present study aimed to identify the association between TMCO1 and lung adenocarcinoma. The present study demonstrated that the positive immunohistochemical staining of TMCO1 in lung adenocarcinoma tissues was significantly higher compared with paracarcinoma tissues. Additionally, knockdown of TMCO1 was demonstrated to downregulate B-cell lymphoma-2 protein expression levels and upregulate cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 protein expression levels in A549 cells. These changes resulted in decreased apoptosis of A549 cells uponTMCO1 downregulation. In addition, knockdown of TMCO1 decreased matrix metalloproteinase (MMP)-2 and MMP-9 expression levels. The expression of N-cadherin and vimentin also decreased. By contrast, the expression levels of E-cadherin protein increased. Knockdown of TMCO1 resulted in the inhibition of A549 cell migration. The results of the present study demonstrated that TMCO1 was associated with lung adenocarcinoma and that inhibition of TMCO1 expression levels negatively regulated the apoptosis and migration of lung adenocarcinoma cells. Therefore, the present study suggests the potential for TMCO1 to be used in the clinical treatment of lung adenocarcinoma.
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Affiliation(s)
- Chen Yang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Yuan Wang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Jian-Qi Bai
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Jing-Ru Zhang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Pei-Yan Hu
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Yan Zhu
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Qin Ouyang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Hong-Mei Su
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Qiu-Yue Li
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
| | - Ping Zhang
- Department of Pathology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, P.R. China
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13
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Calcilytics inhibit the proliferation and migration of human prostate cancer PC-3 cells. J Pharmacol Sci 2019; 139:254-257. [DOI: 10.1016/j.jphs.2019.01.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 01/12/2019] [Accepted: 01/30/2019] [Indexed: 12/11/2022] Open
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14
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Bellamri M, Turesky RJ. Dietary Carcinogens and DNA Adducts in Prostate Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1210:29-55. [PMID: 31900903 DOI: 10.1007/978-3-030-32656-2_2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Prostate cancer (PC) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer-related to death in men. The major risk factors for PC are age, family history, and African American ethnicity. Epidemiological studies have reported large geographical variations in PC incidence and mortality, and thus lifestyle and dietary factors influence PC risk. High fat diet, dairy products, alcohol and red meats, are considered as risk factors for PC. This book chapter provides a comprehensive, literature-based review on dietary factors and their molecular mechanisms of prostate carcinogenesis. A large portion of our knowledge is based on epidemiological studies where dietary factors such as cancer promoting agents, including high-fat, dairy products, alcohol, and cancer-initiating genotoxicants formed in cooked meats have been evaluated for PC risk. However, the precise mechanisms in the etiology of PC development remain uncertain. Additional animal and human cell-based studies are required to further our understandings of risk factors involved in PC etiology. Specific biomarkers of chemical exposures and DNA damage in the prostate can provide evidence of cancer-causing agents in the prostate. Collectively, these studies can improve public health research, nutritional education and chemoprevention strategies.
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Affiliation(s)
- Medjda Bellamri
- Department of Medicinal Chemistry, Cancer and Cardiovascular Research Building, University of Minnesota, Minneapolis, MN, USA.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Robert J Turesky
- Department of Medicinal Chemistry, Cancer and Cardiovascular Research Building, University of Minnesota, Minneapolis, MN, USA. .,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
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Cardoso AL, Fernandes A, Aguilar-Pimentel JA, de Angelis MH, Guedes JR, Brito MA, Ortolano S, Pani G, Athanasopoulou S, Gonos ES, Schosserer M, Grillari J, Peterson P, Tuna BG, Dogan S, Meyer A, van Os R, Trendelenburg AU. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Res Rev 2018; 47:214-277. [PMID: 30071357 DOI: 10.1016/j.arr.2018.07.004] [Citation(s) in RCA: 303] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 07/08/2018] [Accepted: 07/10/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. METHODS Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several "hallmark of aging" pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six "hallmark of aging" pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. RESULTS A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. CONCLUSION Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential.
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Gong X, Li G, Huang Y, Fu Z, Song X, Chen C, Yang L. Synergistically regulated spontaneous calcium signaling is attributed to cartilaginous extracellular matrix metabolism. J Cell Physiol 2018; 234:9711-9722. [PMID: 30370672 DOI: 10.1002/jcp.27657] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/02/2018] [Indexed: 12/13/2022]
Abstract
Ca2+ has been recognized as a key molecule for chondrocytes, however, the role and mechanism of spontaneous [Ca 2+ ] i signaling in cartilaginous extracellular matrix (ECM) metabolism regulation are unclear. Here we found that spontaneous Ca 2+ signal of in-situ porcine chondrocytes was [Ca 2+ ] o dependent, and mediated by [Ca 2+ ] i store release. T-type voltage-dependent calcium channel (T-VDCC) mediated [Ca 2+ ] o influx was associated with decreased cell viability and expression levels of ECM deposition genes. Further analysis revealed that chondrocytes expressed both inositol 1,4,5-trisphosphate receptor (InsP3R) and Orai isoforms. Inhibition of endoplasmic reticulum (ER) Ca 2+ release and store-operated calcium entry significantly abolished spontaneous [Ca 2+ ] i signaling of in-situ chondrocytes. Moreover, blocking ER Ca 2+ release with InsP3R inhibitors significantly upregulated ECM degradation enzymes production, and was accompanied by decreased proteoglycan and collagen type II intensity. Taken together, our data provided evidence that spontaneous [Ca 2+ ] i signaling of in-situ porcine chondrocytes was tightly regulated by [Ca 2+ ] o influx, InsP3Rs mediated [Ca 2+ ] i store release, and Orais mediated calcium release-activated calcium channels activation. Both T-VDCC mediated [Ca 2+ ] o influx and InsP3Rs mediated ER Ca 2+ release were found crucial to cartilaginous ECM metabolism through distinct regulatory mechanisms.
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Affiliation(s)
- Xiaoyuan Gong
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Gaoming Li
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yang Huang
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhenlan Fu
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiongbo Song
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Cheng Chen
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Liu Yang
- Center for Joint Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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Hoorelbeke D, Decrock E, Van Haver V, De Bock M, Leybaert L. Calcium, a pivotal player in photodynamic therapy? BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2018; 1865:1805-1814. [PMID: 30076858 DOI: 10.1016/j.bbamcr.2018.07.022] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 06/28/2018] [Accepted: 07/30/2018] [Indexed: 02/06/2023]
Abstract
Photodynamic therapy combines three non-toxic components: light, oxygen and a photosensitizer to generate singlet oxygen and/or other ROS molecules in order to target destruction of cancer cells. The damage induced in the targeted cells can furthermore propagate to non-exposed bystander cells thereby exacerbating the damage. Ca2+ signaling is strongly intertwined with ROS signaling and both play crucial roles in cell death. In this review we aimed to review current knowledge on the role of Ca2+ and ROS signaling, their effect on cell-cell propagation via connexin-linked mechanisms and the outcome in terms of cell death. In general, photodynamic therapy results in an increased cytosolic Ca2+ concentration originating from Ca2+ entry or Ca2+ release from internal stores. While photodynamic therapy can certainly induce cell death, the outcome depends on the cell type and the photosensitizer used. Connexin channels propagating the Ca2+ signal, and presumably regenerating ROS at distance, may play a role in spreading the effect to neighboring non-exposed bystander cells. Given the various cell types and photosensitizers used, there is currently no unified signaling scheme to explain the role of Ca2+ and connexins in the responses following photodynamic therapy. This article is part of a Special Issue entitled: Calcium signaling in health, disease and therapy edited by Geert Bultynck and Jan Parys.
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Affiliation(s)
| | - Elke Decrock
- Physiology group, Dept. of Basic Medical Sciences, UGent, Ghent, Belgium
| | - Valérie Van Haver
- Physiology group, Dept. of Basic Medical Sciences, UGent, Ghent, Belgium
| | - Marijke De Bock
- Physiology group, Dept. of Basic Medical Sciences, UGent, Ghent, Belgium
| | - Luc Leybaert
- Physiology group, Dept. of Basic Medical Sciences, UGent, Ghent, Belgium.
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The suppressive role of calcium sensing receptor in endometrial cancer. Sci Rep 2018; 8:1076. [PMID: 29348629 PMCID: PMC5773571 DOI: 10.1038/s41598-018-19286-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 09/18/2017] [Indexed: 12/14/2022] Open
Abstract
Studies have shown that calcium sensing receptor (CaSR) is involved in the progressions of several human cancers. However, the role of CaSR in endometrial cancer remains unknown. This study provides a preliminary analysis of the CaSR effect on endometrial cancer development. Ectopic CaSR expression by lentiviral transfection (CaSR-OV) in Ishikawa cells significantly increased intracellular calcium ([Ca2+]i) levels and cell apoptosis. E-cadherin and β-catenin expression and complex formation at the membrane were increased in CaSR-OV Ishikawa cells relative to control Ishikawa cells (vector). Furthermore, CaSR-OV Ishikawa cells showed a reduced invasive potential, which was attributed to E-cadherin/β-catenin complex formation. Moreover, a reduction in CaSR expression in endometrial cancer relative to normal specimens was evident by immunohistochemistry and was positively associated with E-cadherin, but not β-catenin, expression. Furthermore, VEGFR3 was significantly down-regulated in CaSR-OV Ishikawa cells. Additionally, an immunohistochemical analysis showed that VEGFR3 was significantly increased in endometrial cancer compared with the normal endometrium and was inversely correlated with CaSR expression. However, the CaSR knockdown produced the opposite effects. These findings suggest an inhibitory role for CaSR in endometrial cancer. Therefore, reduced CaSR expression may be a suitable explanation and valuable predictor for endometrial cancer progression.
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Smithrud DB, Powers L, Lunn J, Abernathy S, Peschka M, Ho SM, Tarapore P. Ca 2+ Selective Host Rotaxane Is Highly Toxic Against Prostate Cancer Cells. ACS Med Chem Lett 2017; 8:163-167. [PMID: 28197305 DOI: 10.1021/acsmedchemlett.6b00347] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 01/04/2017] [Indexed: 01/09/2023] Open
Abstract
New therapies are needed to eradicate androgen resistant, prostate cancer. Prostate cancer usually metastasizes to bone where the concentration of calcium is high, making Ca2+ a promising toxin. Ionophores can deliver metal cations into cells, but are currently too toxic for human use. We synthesized a new rotaxane (CEHR2) that contains a benzyl 15-crown-5 ether as a blocking group to efficiently bind Ca2+. CEHR2 transfers Ca2+ from an aqueous solution into CHCl3 to greater extent than alkali metal cations and Mg2+. It also transfers Ca2+ to a greater extent than CEHR1, which is a rotaxane with an 18-crown-6 ether as a blocking group. CEHR2 was more toxic against the prostate cancer cell lines PC-3, 22Rv1, and C4-2 than CEHR1. This project demonstrates that crown ether rotaxanes can be designed to bind a targeted metal cation, and this selective cation association can result in enhanced toxicity.
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Affiliation(s)
- David B. Smithrud
- Contribution
from the Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Lucas Powers
- Contribution
from the Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Jennifer Lunn
- Contribution
from the Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Scott Abernathy
- Contribution
from the Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Michael Peschka
- Contribution
from the Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Shuk-mei Ho
- Cincinnati Veterans Affairs Medical Center, 3200 Vine Street, Cincinnati, Ohio 45220, United States
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Marques R, Peres CG, Vaz CV, Gomes IM, Figueira MI, Cairrão E, Verde I, Maia CJ, Socorro S. 5α-Dihydrotestosterone regulates the expression of L-type calcium channels and calcium-binding protein regucalcin in human breast cancer cells with suppression of cell growth. Med Oncol 2015; 32:228. [PMID: 26255063 DOI: 10.1007/s12032-015-0676-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 08/03/2015] [Indexed: 12/20/2022]
Abstract
Androgens have been associated with the development of normal breast, and their role in mammary gland carcinogenesis has also been described. Several studies reported that androgens inhibit breast cancer cell growth, whereas others linked their action with the modulation of calcium (Ca(2+)) pumps, Ca(2+) channels and Ca(2+)-binding proteins. Also, it is known that deregulated Ca(2+) homeostasis has been implicated in the pathophysiology of breast. The L-type Ca(2+) channels (LTCCs) were found to be up-regulated in colon, colorectal and prostate cancer, but their presence in breast tissues remains uncharacterized. On the other hand, regucalcin (RGN) is a Ca(2+)-binding protein involved in the control of mammary gland cell proliferation, which has been identified as an androgen target gene in distinct tissues except breast. This study aimed to confirm the expression and activity of LTCCs in human breast cancer cells and investigate the effect of androgens in regulating the expression of α1C subunit (Cav1.2) of LTCCs and Ca(2+)-binding protein RGN. PCR, Western blot, immunofluorescence and electrophysiological experiments demonstrated the expression and activity of Cav1.2 subunit in MCF-7 cells. The MCF-7 cells were treated with 1, 10 or 100 nM of 5α-dihydrotestosterone (DHT) for 24-72 h. The obtained results showed that 1 nM DHT up-regulated the expression of Cav1.2 subunit while diminishing RGN protein levels, which was underpinned by reduced cell viability. These findings first confirmed the presence of LTCCs in breast cancer cells and opened new perspectives for the development of therapeutic approaches targeting Ca(2+) signaling.
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Affiliation(s)
- Ricardo Marques
- Faculdade de Ciências da Saúde, CICS-UBI - Health Sciences Research Center, University of Beira Interior, Av. Infante D. Henrique, 6200-506, Covilhã, Portugal
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