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1
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Peri S, Niv Y. Estrogen receptor beta (ERβ) in esophageal cancer - a systematic review and meta-analysis. Scand J Gastroenterol 2024; 59:1178-1183. [PMID: 39192713 DOI: 10.1080/00365521.2024.2396479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/11/2024] [Accepted: 08/20/2024] [Indexed: 08/29/2024]
Abstract
BACKGROUND Esophageal cancer is the eighth most common cause of cancer-related deaths worldwide. There are two main histological subtypes of esophageal cancer: adenocarcinoma and squamous cell carcinoma. Among the factors associated with the development of esophageal cancer, estrogen receptor beta (ERβ) has been found to have a clinical significance. AIM To investigate the relationship between ERβ expression and esophageal cancer. METHODS English Medical literature searches were conducted for ERβ expression in patients with esophageal cancer versus healthy controls. Searches were performed up to August 31, 2023, using MEDLINE, PubMed, Embase and Google Scholar. Meta-analysis was performed by using Comprehensive meta-analysis software (Version 4, Biostat Inc., Englewood, NJ, USA). Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated. Heterogeneity was evaluated using Cochrane Q-test, and it was considered present if the Q-test P value was less than 0.10. I2 statistic was used to measure the proportion of inconsistency in individual studies, with I2 > 50% representing heterogeneity. We also calculated a potential publication bias. RESULTS Ten studies representing 11 substudies were selected according to the inclusion criteria. The odds ratio of ERβ expression in fixed effect analysis was 0.448, 95% CI: 0.237 to 0.846, 55.2% lower in esophageal cancer than in normal mucosa. Heterogeneity and inconsistency were low, and no publication bias was demonstrated. CONCLUSION This meta-analysis showed that ERβ expression is lower in esophageal cancer biopsy specimens than in healthy controls, this finding may have a significant effect on survival and can lead to new therapeutic avenues.
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Affiliation(s)
- Shir Peri
- Adelson Faculty of Medicine, Ariel University, Israel
| | - Yaron Niv
- Adelson Faculty of Medicine, Ariel University, Israel
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2
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Kołodziejska R, Tafelska-Kaczmarek A, Pawluk M, Sergot K, Pisarska L, Woźniak A, Pawluk H. Ashwagandha-Induced Programmed Cell Death in the Treatment of Breast Cancer. Curr Issues Mol Biol 2024; 46:7668-7685. [PMID: 39057095 PMCID: PMC11275341 DOI: 10.3390/cimb46070454] [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: 06/21/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 07/28/2024] Open
Abstract
The aim of this review is to provide experimental evidence for the programmed-death activity of Ashwagandha (Withania somnifera) in the anti-cancer therapy of breast cancer. The literature search was conducted using online electronic databases (Google Scholar, PubMed, Scopus). Collection schedule data for the review article covered the years 2004-2024. Ashwagandha active substances, especially Withaferin A (WA), are the most promising anti-cancer compounds. WS exerts its effect on breast cancer cells by inducing programmed cell death, especially apoptosis, at the molecular level. Ashwagandha has been found to possess a potential for treating breast cancer, especially estrogen receptor/progesterone receptor (ER/PR)-positive and triple-negative breast cancer.
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Affiliation(s)
- Renata Kołodziejska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Agnieszka Tafelska-Kaczmarek
- Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland;
| | - Mateusz Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Krzysztof Sergot
- Laboratory of Laser Molecular Spectroscopy, Institute of Applied Radiation Chemistry, Faculty of Chemistry, Lodz University of Technology, Wroblewskiego 15, 93-590 Lodz, Poland;
| | - Lucyna Pisarska
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Alina Woźniak
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
| | - Hanna Pawluk
- Department of Medical Biology and Biochemistry, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Karłowicza 24, 85-092 Bydgoszcz, Poland; (M.P.); (L.P.); (H.P.)
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Wu J, Bai Y, Lu Y, Yu Z, Zhang S, Yu B, Chen L, Li J. Role of sex steroids in colorectal cancer: pathomechanisms and medical applications. Am J Cancer Res 2024; 14:3200-3221. [PMID: 39113870 PMCID: PMC11301278 DOI: 10.62347/oebs6893] [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: 03/29/2024] [Accepted: 06/26/2024] [Indexed: 08/10/2024] Open
Abstract
Given that the colon represents the most extensive hormone-responsive tissue in the human body, it prompts a compelling inquiry into whether the progression of its cancer is intimately linked to hormonal dynamics. Consequently, the interplay between sex steroids - a pivotal constituent of hormones - and colorectal cancer has increasingly captivated scientific interest. Upon a comprehensive review of pertinent literature both domestically and internationally, this study delineates the present landscape of three pivotal steroids - estrogen, progestin, and androgen - in the context of colorectal cancer. More specifically, this investigation probes into the potential utility of these steroids in providing therapeutic interventions, diagnostic insights, and prognostic indicators. Furthermore, this study also delves into the mechanistic pathways through which sex steroid interventions exert influence on colorectal cancer. It was discovered that the trio of sex steroid hormones partakes in an array of biological processes, thereby influencing the onset and progression of colorectal cancer. In conclusion, this study posits that a profound interconnection exists between colorectal cancer and sex steroids, suggesting that elucidating the targets of their action mechanisms could unveil novel avenues for the diagnosis and prevention of colorectal cancer.
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Affiliation(s)
- Jianglan Wu
- Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
| | - Yanan Bai
- Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
| | - Yuwen Lu
- Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
| | - Zixuan Yu
- Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
| | - Shumeng Zhang
- Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
| | - Bin Yu
- Department of Gastroenterology, The First Affiliated Hospital of Hunan University of Traditional Chinese MedicineChangsha 410007, Hunan, China
| | - Lingli Chen
- Hunan Provincial Key Laboratory of Pathogenic Biology Based on Integrated Chinese and Western Medicine, Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
| | - Jie Li
- Hunan University of Traditional Chinese MedicineChangsha 410208, Hunan, China
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4
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Li H, Seada H, Madnick S, Zhao H, Chen Z, Li F, Zhu F, Hall S, Boekelheide K. Machine learning-assisted high-content imaging analysis of 3D MCF7 microtissues for estrogenic effect prediction. Sci Rep 2024; 14:2999. [PMID: 38316851 PMCID: PMC10844358 DOI: 10.1038/s41598-024-53323-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/30/2024] [Indexed: 02/07/2024] Open
Abstract
Endocrine-disrupting chemicals (EDCs) pose a significant threat to human well-being and the ecosystem. However, in managing the many thousands of uncharacterized chemical entities, the high-throughput screening of EDCs using relevant biological endpoints remains challenging. Three-dimensional (3D) culture technology enables the development of more physiologically relevant systems in more realistic biochemical microenvironments. The high-content and quantitative imaging techniques enable quantifying endpoints associated with cell morphology, cell-cell interaction, and microtissue organization. In the present study, 3D microtissues formed by MCF-7 breast cancer cells were exposed to the model EDCs estradiol (E2) and propyl pyrazole triol (PPT). A 3D imaging and image analysis pipeline was established to extract quantitative image features from estrogen-exposed microtissues. Moreover, a machine-learning classification model was built using estrogenic-associated differential imaging features. Based on 140 common differential image features found between the E2 and PPT group, the classification model predicted E2 and PPT exposure with AUC-ROC at 0.9528 and 0.9513, respectively. Deep learning-assisted analysis software was developed to characterize microtissue gland lumen formation. The fully automated tool can accurately characterize the number of identified lumens and the total luminal volume of each microtissue. Overall, the current study established an integrated approach by combining non-supervised image feature profiling and supervised luminal volume characterization, which reflected the complexity of functional ER signaling and highlighted a promising conceptual framework for estrogenic EDC risk assessment.
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Affiliation(s)
- Hui Li
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Zhejiang University, 866 Yuhangtang Rd, Hangzhou, 310058, China.
- Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, RI, 02903, USA.
| | - Haitham Seada
- Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, RI, 02903, USA
| | - Samantha Madnick
- Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, RI, 02903, USA
| | - He Zhao
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Zhejiang University, 866 Yuhangtang Rd, Hangzhou, 310058, China
| | - Zhaozeng Chen
- College of Pharmaceutical Sciences, Center for Drug Safety Evaluation and Research of Zhejiang University, Zhejiang University, 866 Yuhangtang Rd, Hangzhou, 310058, China
| | - Fengcheng Li
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Feng Zhu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Susan Hall
- Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, RI, 02903, USA
| | - Kim Boekelheide
- Department of Pathology and Laboratory Medicine, Brown University, 70 Ship Street, Providence, RI, 02903, USA.
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Harvey BJ, Harvey HM. Sex Differences in Colon Cancer: Genomic and Nongenomic Signalling of Oestrogen. Genes (Basel) 2023; 14:2225. [PMID: 38137047 PMCID: PMC10742859 DOI: 10.3390/genes14122225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/10/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Colon cancer (CRC) is a prevalent malignancy that exhibits distinct differences in incidence, prognosis, and treatment responses between males and females. These disparities have long been attributed to hormonal differences, particularly the influence of oestrogen signalling. This review aims to provide a comprehensive analysis of recent advances in our understanding of the molecular mechanisms underlying sex differences in colon cancer and the protective role of membrane and nuclear oestrogen signalling in CRC development, progression, and therapeutic interventions. We discuss the epidemiological and molecular evidence supporting sex differences in colon cancer, followed by an exploration of the impact of oestrogen in CRC through various genomic and nongenomic signalling pathways involving membrane and nuclear oestrogen receptors. Furthermore, we examine the interplay between oestrogen receptors and other signalling pathways, in particular the Wnt/β-catenin proliferative pathway and hypoxia in shaping biological sex differences and oestrogen protective actions in colon cancer. Lastly, we highlight the potential therapeutic implications of targeting oestrogen signalling in the management of colon cancer and propose future research directions to address the current gaps in our understanding of this complex phenomenon.
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Affiliation(s)
- Brian J. Harvey
- Faculty of Medicine, Royal College of Surgeons in Ireland, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland
| | - Harry M. Harvey
- Princess Margaret Cancer Centre, Toronto, ON M5G 1Z5, Canada;
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Alatawi FS, Faridi U. Anticancer and anti-metastasis activity of 1,25 dihydroxycholecalciferols and genistein in MCF-7 and MDA-MB-231 breast cancer cell lines. Heliyon 2023; 9:e21975. [PMID: 38034665 PMCID: PMC10682641 DOI: 10.1016/j.heliyon.2023.e21975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 11/01/2023] [Accepted: 11/01/2023] [Indexed: 12/02/2023] Open
Abstract
A powerful steroid hormone precursor, 1,25 dihydroxycholecalciferols (1,25(OH)2D3), and dietary phytoestrogen (genistein) are essential compounds that act by binding to nuclear receptors and altering gene expression. They have many biological benefits, some of which have anticancer properties. We studied the impact of 1,25(OH)2D3 and genistein on the proliferation, progression, and metastasis of MCF-7 and MDA-MB-231 cells when they were used alone or in combination and investigated whether there was a synergistic effect between genistein and 1,25(OH)2D3. To achieve these goals, a variety of assays, including flow cytometry, cell invasion assays, cell adhesion assays, Western blotting, and RT‒PCR, were used. Our findings showed that genistein, 1,25(OH)2D3, and the two combined all effectively declined the growth of MCF-7 and MDA-MB-231 cells by arresting the cells in the G0/G1 phase and inducing an apoptotic pathway. Stimulation of apoptosis was achieved by upregulating the expression of BAX and CASP3 genes and downregulating the expression levels of BCL-2 gene. Furthermore, both compounds suppress metastasis by reducing cell adhesion and cell migration/invasion by elevating the expression level of E-cadherin and reducing the expression level of P-cadherin and N-cadherin. Additionally, both genistein and 1,25(OH)2D3 increased the expression level of ERK1 and reduced the expression levels of JNK, p38, Ras, and MEK proteins, which reduced metastasis, enhanced the response to cancer treatment, and improved overall survival. Thus, genistein and 1,25(OH)2D3 can both be considered key candidates in the search for new breast cancer treatments.
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Affiliation(s)
- Fatema Suliman Alatawi
- Faculty of Sciences, Biochemistry Department, Science College, University of Tabuk, Tabuk Saudi Arabia
| | - Uzma Faridi
- Faculty of Sciences, Biochemistry Department, Science College, University of Tabuk, Tabuk Saudi Arabia
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Yuk JS, Yang SW, Yoon SH, Kim MH, Seo YS, Lee Y, Kim J, Yang K, Gwak G, Cho H. The increased risk of colorectal cancer in the women who underwent hysterectomy from the South Korean National Health Insurance Database. BMC Womens Health 2023; 23:519. [PMID: 37775754 PMCID: PMC10542264 DOI: 10.1186/s12905-023-02642-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 09/08/2023] [Indexed: 10/01/2023] Open
Abstract
BACKGROUND Several population-based studies and observational studies have shown that oophorectomy is associated with an increased risk of colorectal cancer (CRC), and hormone replacement therapy has been associated with a reduction in the risk of colorectal cancer. This study was carried out to investigate whether hysterectomy, which may affect the levels of female hormones, is associated with a risk of cancer of the specific gastrointestinal tract. METHODS This population-based retrospective cohort study was conducted using insurance data provided by the Health Insurance Review and Assessment Service (HIRA) from January 1, 2007, to December 31, 2020. The hysterectomy group included 40- to 59-year-old women who underwent hysterectomy with uterine leiomyoma or uterine endometriosis from January 1, 2011, to December 31, 2014. The control group included women aged 40 to 59 years who visited medical institutions for medical examination from January 1, 2011 to December 31, 2014. RESULTS The hysterectomy and non-hysterectomhy groups comprised 66,204 and 89,768 subjects, respectively. The median ages in the non-hysterectomy group and hysterectomy group were 48 (range: 43-53) and 46 (range: 44-49) years, respectively. In the unadjusted results of the analysis, all colorectal cancer (CRC) increased in the hysterectomy alone group (HR 1.222, 95% confidence interval (CI) 1.016-1.47, p = 0.033), sigmoid colon cancer increased in the hysterectomy alone group (HR 1.71, 95% CI 1.073-2.724, p = 0.024), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.924, 95% CI 1.073-2.724, p = 0.002). The adjusted results showed that all CRC increased in the hysterectomy alone group (HR 1.406, 95% CI 1.057-1.871, p = 0.019), colon cancer increased in the hysterectomy alone group (HR 1.523, 95% CI 1.068-2.17, p = 0.02), and rectal cancer increased in the hysterectomy with adnexal surgery group (HR 1.933, 95% CI 1.131-3.302, p = 0.016). The all-cause mortality of GI cancer increased in the hysterectomy alone group (HR 3.495, 95% CI 1.347-9.07, p = 0.001). CONCLUSIONS This study showed that the risk of all CRC increased in women who underwent hysterectomy compared with women who did not. In particular, the risk of rectal cancer was significantly higher in the women who underwent hysterectomy with adnexal surgery than in the controls. There was no association between hysterectomy and other GI cancers.
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Affiliation(s)
- Jin -Sung Yuk
- Department of Obstetrics and Gynecology, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Seung-Woo Yang
- Department of Obstetrics and Gynecology, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Sang-Hee Yoon
- Department of Obstetrics and Gynecology, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Myoung Hwan Kim
- Department of Obstetrics and Gynecology, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Yong-Soo Seo
- Department of Obstetrics and Gynecology, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Yujin Lee
- Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Jungbin Kim
- Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Keunho Yang
- Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Geumhee Gwak
- Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea
| | - Hyunjin Cho
- Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University, Seoul, Republic of Korea.
- Department of Surgery, Sanggye Paik Hospital, School of Medicine, Inje University, Dongil-Ro, Nowon-Gu, Seoul, 1342, Republic of Korea.
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8
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Stanczyk FZ, Mandelbaum RS, Matharu H, Dancz CE, Sherman ME. Endometrial safety of low-dose vaginal estrogens. Menopause 2023; 30:650-658. [PMID: 37022294 DOI: 10.1097/gme.0000000000002177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023]
Abstract
ABSTRACT It is estimated that up to 50% to 90% of postmenopausal women may experience genitourinary syndrome of menopause (GSM), which may have a detrimental impact on quality of life. One of the most effective modes of treatment of GSM is low-dose vaginal estrogens. Numerous studies have addressed the safety of these estrogens using endometrial biopsy and/or endometrial thickness on ultrasound. Based on these studies, the consensus is that low-dose vaginal estrogens do not substantially increase the risk of endometrial hyperplasia or cancer; however, the data are severely limited by short duration of follow-up. Although long-term trials are warranted, they are difficult to carry out, costly, and will not yield data for years. More immediate information regarding endometrial safety may be obtained from studies measuring endometrial tissue and serum concentrations of estradiol, estrone, and relevant equine estrogens after administration of different estrogen formulations and doses. This would allow us to understand better the metabolism of estrogens by the vagina and endometrium, and how much estrogen is reaching the endometrium. Here, we discuss metabolism, receptor binding, and signaling of estrogens in vaginal and endometrial tissue, and summarize the existing studies on the endometrial impact of low-dose vaginal estrogen treatment in postmenopausal women.
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Affiliation(s)
- Frank Z Stanczyk
- From the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA
| | - Rachel S Mandelbaum
- From the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA
| | - Harpreet Matharu
- From the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA
| | - Christina E Dancz
- From the Department of Obstetrics and Gynecology, University of Southern California, Keck School of Medicine, Los Angeles, CA
| | - Mark E Sherman
- Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL
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Ditonno I, Novielli D, Celiberto F, Rizzi S, Rendina M, Ierardi E, Di Leo A, Losurdo G. Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis. Int J Mol Sci 2023; 24:ijms24065687. [PMID: 36982759 PMCID: PMC10056005 DOI: 10.3390/ijms24065687] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/11/2023] [Accepted: 03/15/2023] [Indexed: 03/19/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.
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Affiliation(s)
- Ilaria Ditonno
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Domenico Novielli
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Francesca Celiberto
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
- Course in Organs and Tissues Transplantation and Cellular Therapies, Department of Precision Medicine Jonic Area, University “Aldo Moro” of Bari, 70124 Bari, Italy
| | - Salvatore Rizzi
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Maria Rendina
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Enzo Ierardi
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Giuseppe Losurdo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
- Correspondence:
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10
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Huang D, Berglund M, Damdimopoulos A, Antonson P, Lindskog C, Enblad G, Amini RM, Okret S. Sex- and Female Age-Dependent Differences in Gene Expression in Diffuse Large B-Cell Lymphoma-Possible Estrogen Effects. Cancers (Basel) 2023; 15:cancers15041298. [PMID: 36831639 PMCID: PMC9954534 DOI: 10.3390/cancers15041298] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/09/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
For most lymphomas, including diffuse large B-cell lymphoma (DLBCL), the male incidence is higher, and the prognosis is worse compared to females. The reasons are unclear; however, epidemiological and experimental data suggest that estrogens are involved. With this in mind, we analyzed gene expression data from a publicly available cohort (EGAD00001003600) of 746 DLBCL samples based on RNA sequencing. We found 1293 genes to be differentially expressed between males and females (adj. p-value < 0.05). Few autosomal genes and pathways showed common sex-regulated expression between germinal center B-cell (GCB) and activated B-cell lymphoma (ABC) DLBCL. Analysis of differentially expressed genes between pre- vs. postmenopausal females identified 208 GCB and 345 ABC genes, with only 5 being shared. When combining the differentially expressed genes between females vs. males and pre- vs. postmenopausal females, nine putative estrogen-regulated genes were identified in ABC DLBCL. Two of them, NR4A2 and MUC5B, showed induced and repressed expression, respectively. Interestingly, NR4A2 has been reported as a tumor suppressor in lymphoma. We show that ABC DLBCL females with a high NR4A2 expression showed better survival. Inversely, MUC5B expression causes a more malignant phenotype in several cancers. NR4A2 and MUC5B were confirmed to be estrogen-regulated when the ABC cell line U2932 was grafted to mice. The results demonstrate sex- and female reproductive age-dependent differences in gene expression between DLBCL subtypes, likely due to estrogens. This may contribute to the sex differences in incidence and prognosis.
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Affiliation(s)
- Dan Huang
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden
| | - Mattias Berglund
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden
| | - Anastasios Damdimopoulos
- Bioinformatics and Expression Core Facility, Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden
| | - Per Antonson
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden
| | - Cecilia Lindskog
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden
| | - Gunilla Enblad
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden
| | - Rose-Marie Amini
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden
| | - Sam Okret
- Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 83 Huddinge, Sweden
- Correspondence: ; Tel.: +46-8-524-81069
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11
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Choi E, Mun GI, Lee J, Lee H, Cho J, Lee YS. BRCA1 deficiency in triple-negative breast cancer: Protein stability as a basis for therapy. Biomed Pharmacother 2023; 158:114090. [PMID: 36493696 DOI: 10.1016/j.biopha.2022.114090] [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: 10/24/2022] [Revised: 11/24/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Mutations in breast cancer-associated 1 (BRCA1) increase the lifetime risk of developing breast cancer by up to 51% over the risk of the general population. Many aspects of this multifunctional protein have been revealed, including its essential role in homologous recombination repair, E3 ubiquitin ligase activity, transcriptional regulation, and apoptosis. Although most studies have focused on BRCA1 deficiency due to mutations, only a minority of patients carry BRCA1 mutations. A recent study has suggested an expanded definition of BRCA1 deficiency with reduced BRCA1 levels, which accounts for almost half of all triple-negative breast cancer (TNBC) patients. Reduced BRCA1 levels can result from epigenetic modifications or increased proteasomal degradation. In this review, we discuss how this knowledge of BRCA1 function and regulation of BRCA1 protein stability can help overcome the challenges encountered in the clinic and advance current treatment strategies for BRCA1-related breast cancer patients, especially focusing on TNBC.
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Affiliation(s)
- Eun Choi
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Gil-Im Mun
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Joohyun Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Hanhee Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea
| | - Jaeho Cho
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Yun-Sil Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
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12
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Das PK, Saha J, Pillai S, Lam AKY, Gopalan V, Islam F. Implications of estrogen and its receptors in colorectal carcinoma. Cancer Med 2023; 12:4367-4379. [PMID: 36207986 PMCID: PMC9972078 DOI: 10.1002/cam4.5242] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/18/2022] [Accepted: 09/01/2022] [Indexed: 11/08/2022] Open
Abstract
Estrogens have been implicated in the pathogenesis of various cancer types, including colorectal carcinoma (CRC). Estrogen receptors such as ERα and ERβ activate intracellular signaling cascades followed by binding to estrogen, resulting in important changes in cellular behaviors. The nuclear estrogen receptors, i.e. ERβ and ERα are responsible for the genomic actions of estrogens, whereas the other receptor, such as G protein-coupled estrogen receptor (GPER) regulates rapid non-genomic actions, which lead to secondary gene expression changes in cells. ERβ, the predominant estrogen receptor expressed in both normal and non-malignant colonic epithelium, has protective roles in colon carcinogenesis. ERβ may exert the anti-tumor effect through selective activation of pro-apoptotic signaling, increasing DNA repair, inhibiting expression of oncogenes, regulating cell cycle progression, and also by changing the micro-RNA pool and DNA-methylation. Thus, a better understanding of the underlying mechanisms of estrogen and its receptors in CRC pathogenesis could provide a new horizon for effective therapeutic development. Furthermore, using synthetic or natural compounds as ER agonists may induce estrogen-mediated anti-cancer activities against colon cancer. In this study, we report the most recent pre-clinical and experimental evidences related to ERs in CRC development. Also, we reviewed the actions of naturally occurring and synthetic compounds, which have a protective role against CRC development by acting as ER agonist.
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Affiliation(s)
- Plabon Kumar Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.,Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia
| | - Joti Saha
- Department of Applied Chemistry and Chemical Engineering, University of Rajshahi, Rajshahi, Bangladesh
| | - Suja Pillai
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Alfred K-Y Lam
- School of Medicine & Dentistry, Griffith University, Gold Coast, Queensland, Australia
| | - Vinod Gopalan
- School of Medicine & Dentistry, Griffith University, Gold Coast, Queensland, Australia
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh.,Institute for Glycomics, Griffith University, Gold Coast, Queensland, Australia
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13
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Cipolletti M, Leone S, Bartoloni S, Acconcia F. A functional genetic screen for metabolic proteins unveils GART and the de novo purine biosynthetic pathway as novel targets for the treatment of luminal A ERα expressing primary and metastatic invasive ductal carcinoma. Front Endocrinol (Lausanne) 2023; 14:1129162. [PMID: 37143728 PMCID: PMC10151738 DOI: 10.3389/fendo.2023.1129162] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/31/2023] [Indexed: 05/06/2023] Open
Abstract
Targeting tumor cell metabolism is a new frontier in cancer management. Thus, metabolic pathway inhibitors could be used as anti-estrogen receptor α (ERα) breast cancer (BC) drugs. Here, the interplay among metabolic enzyme(s), the ERα levels and cell proliferation was studied. siRNA-based screen directed against different metabolic proteins in MCF10a, MCF-7 and MCF-7 cells genetically resistant to endocrine therapy (ET) drugs and metabolomic analyses in numerous BC cell lines unveil that the inhibition of GART, a key enzyme in the purine de novo biosynthetic pathway, induces ERα degradation and prevent BC cell proliferation. We report here that a reduced GART expression correlates with a longer relapse-free-survival (RFS) in women with ERα-positive BCs. ERα-expressing luminal A invasive ductal carcinomas (IDCs) are sensitive to GART inhibition and GART expression is increased in receptor-positive IDCs of high grade and stage and plays a role in the development of ET resistance. Accordingly, GART inhibition reduces ERα stability and cell proliferation in IDC luminal A cells where it deregulates 17β-estradiol (E2):ERα signaling to cell proliferation. Moreover, the GART inhibitor lometrexol (LMX) and drugs approved for clinical treatment of primary and metastatic BC (4OH-tamoxifen and the CDK4/CDK6 inhibitors) exert synergic antiproliferative effects in BC cells. In conclusion, GART inhibition by LMX or other inhibitors of the de novo purine biosynthetic pathway could be a novel effective strategy for the treatment of primary and metastatic BCs.
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14
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Refaat B, Aslam A, Idris S, Almalki AH, Alkhaldi MY, Asiri HA, Almaimani RA, Mujalli A, Minshawi F, Alamri SA, AlHussain MI, Baltow BA, Alqasmi MH, Basfar GT, Alosaimi OM, Muhayya IA. Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness. Front Endocrinol (Lausanne) 2023; 14:1187259. [PMID: 37206439 PMCID: PMC10190606 DOI: 10.3389/fendo.2023.1187259] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
Background Although estrogen (ERα/ERβ), progesterone (PGR), and androgen (AR) receptors are pathologically altered in colorectal cancer (CRC), their simultaneous expression within the same cohort of patients was not previously measured. Methods ERα/ERβ/PGR/AR proteins were measured in archived paired normal and malignant colon specimens (n =120 patients) by immunohistochemistry, and results were analyzed by gender, age (≤50 vs. ≥60 years), clinical stages (early-stage I/II vs. late-stage III/IV), and anatomical location (right; RSCs vs. left; LSCs). Effects of 17β-estradiol (E2), progesterone (P4), and testosterone alone or combined with the specific blockers of ERα (MPP dihydrochloride), ERβ (PHTPP), PGR (mifepristone), and AR (bicalutamide) on cell cycle and apoptosis were also measured in the SW480 male and HT29 female CRC cell lines. Results ERα and AR proteins increased, whilst ERβ and PGR declined markedly in malignant specimens. Moreover, male neoplastic tissues showed highest AR expression, whilst ERβ and PGR weakest alongside ERα strongest expression was seen in cancerous tissues from women aged ≥60 years. Late-stage neoplasms also revealed maximal alterations in the expression of sex steroid receptors. By tumor location, LSCs disclosed significant elevations in ERα with marked declines in PGR compared with RSCs, and ERα strongest alongside PGR weakest expression was detected in advanced LSCs from women aged ≥60 years. Late-stage LSCs from females aged ≥60 years also showed weakest ERβ and strongest AR expression. In contrast, male RSC and LSC tissues exhibited equal ERβ and AR expression in all clinical stages. ERα and AR proteins also correlated positively, whereas ERβ and PGR inversely, with tumor characteristics. Concomitantly, E2 and P4 monotherapies triggered cell cycle arrest and apoptosis in the SW480 and HT29 cells, and while pre-treatment with ERα-blocker enhanced the effects of E2, ERβ-blocker and PGR-blocker suppressed the E2 and P4 anti-cancer actions, respectively. In contrast, treatment with the AR-blocker induced apoptosis, whilst co-treatment with testosterone hindered the effects. Conclusions This study advocates that protein expression of sex steroid receptors in malignant tissues could represent prognostic markers, as well as hormonal therapy could provide an alternative strategy against CRC, and their efficacies could be dependent on gender, clinical stage, and tumor location.
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Affiliation(s)
- Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- *Correspondence: Bassem Refaat, ;
| | - Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ahmed H. Almalki
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Regional Laboratory and Central Blood Bank, Ministry of Health, Jizan, Saudi Arabia
| | - Mofareh Y. Alkhaldi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Laboratory And Blood Bank Department, Asir Central Hospital, Abha, Saudi Arabia
| | - Hassan A. Asiri
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Forensic Medicine Department, Health Affairs General Directorate in Assir, Abha, Saudi Arabia
| | - Riyad A. Almaimani
- Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdulrahman Mujalli
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Faisal Minshawi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Sara A. Alamri
- Histopathology Department, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Mona I. AlHussain
- Histopathology Department, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Badee A. Baltow
- Histopathology Department, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Mansour H. Alqasmi
- Clinical Laboratories, Al-Noor Specialist Hospital, Makkah, Saudi Arabia
| | - Ghaiyda T. Basfar
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Clinical Laboratories, Al-Noor Specialist Hospital, Makkah, Saudi Arabia
| | - Ohoud M. Alosaimi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Clinical Laboratories, Eradah and Mental Health Complex, Ministry of Health, Taif, Saudi Arabia
| | - Ibrahim A. Muhayya
- Laboratory And Blood Bank Department, Asir Central Hospital, Abha, Saudi Arabia
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15
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Zhu L, Liu S, Liao YF, Sheng YM, He JC, Cai ZX, Man Q, Wu YY. Calycosin suppresses colorectal cancer progression by targeting ERβ, upregulating PTEN, and inhibiting PI3K/Akt signal pathway. Cell Biol Int 2022; 46:1367-1377. [PMID: 35842774 DOI: 10.1002/cbin.11840] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 01/14/2022] [Accepted: 01/22/2022] [Indexed: 12/17/2022]
Abstract
High intake of phytoestrogen has been reported to be associated with the prevention of colorectal cancer (CRC). Calycosin belongs to the phytoestrogen that has been shown to suppress CRC cells in our previous study. However, its anticancer activity and molecular mechanisms have not been elucidated. In this study, we analyzed the effect of calycosin on the viability and apoptosis of human CRC HCT116 and SW480 cells via MTT assay, flow cytometry assay, and caspase-3/7 activity assay. The protein expressions of estrogen receptor β (ERβ), PTEN, and PI3K/Akt signal pathways were determined by Western blot analysis. And then, the alterations of biological behavior in CRC cells transfected with ERβ siRNA were analyzed. Mouse xenograft models were further performed to detect the antitumor effect in vivo. The results show that calycosin reduces CRC cell viability, induces cell apoptosis, and suppresses xenograft tumor growth. The protein expressions of ERβ and PTEN are significantly upregulated following calycosin treatment, whereas p-AKT/AKT ratio and Bcl-2 level are downregulated. Suppressing ERβ with siRNA partially attenuates the reduction in viability and apoptosis induced by calycosin. Our results indicate that calycosin shows inhibitory effects on CRC cells, which might be obtained by targeting ERβ, upregulating PTEN, and inhibiting the PI3K/Akt signal pathway.
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Affiliation(s)
- Lin Zhu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Sha Liu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Yi-Fan Liao
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Yan-Mei Sheng
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Ji-Chun He
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China
| | - Zheng-Xue Cai
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Qiong Man
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
| | - Yi-Ying Wu
- Department of Pharmacology, School of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China.,Department of Pharmacy, Study on the Structure-Specific Small Molecule Drug in Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, Sichuan, China
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16
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Schönemann AM, Beiras R, Diz AP. Widespread alterations upon exposure to the estrogenic endocrine disruptor ethinyl estradiol in the liver proteome of the marine male fish Cyprinodon variegatus. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2022; 248:106189. [PMID: 35537357 DOI: 10.1016/j.aquatox.2022.106189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 04/18/2022] [Accepted: 05/02/2022] [Indexed: 06/14/2023]
Abstract
Quantitative proteomic changes in the liver of adult males of Sheepshead minnow (Cyprinodon variegatus) upon exposure to ethinyl estradiol (EE2) were assessed to provide an advanced understanding of the metabolic pathways affected by estrogenic endocrine disruption in marine fish, and to identify potential novel molecular biomarkers for the environmental exposure to estrogens. From a total of 3188 identified protein groups (hereafter proteins), 463 showed a statistically significant difference in their abundance between EE2 treatment and solvent control samples. The most affected biological processes upon EE2 exposure were related to ribosomal biogenesis, protein synthesis and transport of nascent proteins to endoplasmic reticulum, and nuclear mRNA catabolism. Within the group of upregulated proteins, a subset of 14 proteins, involved in egg production (Vitellogenin, Zona Pellucida), peptidase activity (Cathepsine E, peptidase S1, Serine/threonine-protein kinase PRP4 homolog, Isoaspartyl peptidase and Whey acidic protein), and nucleic acid binding (Poly [ADP-ribose] polymerase 14) were significantly upregulated with fold-change values higher than 3. In contrast, Collagen alpha-2, involved in the process of response to steroid hormones, among others, was significantly downregulated (fold change = 0.2). This pattern of alterations in the liver proteome of adult males of C. variegatus can be used to identify promising novel biomarkers for the characterization of exposure of marine fish to estrogens. The Whey acidic protein-like showed the highest upregulation in EE2-exposed individuals (21-fold over controls), suggesting the utility of abundance levels of this protein in male liver as a novel biomarker of xenoestrogen exposure.
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Affiliation(s)
- Alexandre M Schönemann
- Centro de Investigación Mariña da Universidade de Vigo (CIM-UVigo), Vigo, Galicia, Spain; Department of Biochemistry, Genetics and Immunology, University of Vigo, Vigo, Spain
| | - Ricardo Beiras
- Centro de Investigación Mariña da Universidade de Vigo (CIM-UVigo), Vigo, Galicia, Spain; Department of Ecology and Animal Biology, University of Vigo, Vigo, Galicia, Spain
| | - Angel P Diz
- Centro de Investigación Mariña da Universidade de Vigo (CIM-UVigo), Vigo, Galicia, Spain; Department of Biochemistry, Genetics and Immunology, University of Vigo, Vigo, Spain.
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17
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Therapeutic Strategies and Potential Actions of Female Sex Steroid Hormones and Their Receptors in Colon Cancer Based on Preclinical Studies. Life (Basel) 2022; 12:life12040605. [PMID: 35455096 PMCID: PMC9032023 DOI: 10.3390/life12040605] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/09/2022] [Accepted: 04/14/2022] [Indexed: 11/17/2022] Open
Abstract
Several epidemiological studies have reported that the use of female sex steroid hormones could reduce the risk of colon cancer (CRC). This review summarizes the available data related to estradiol (E2) and progesterone (P4) single and dual treatments in CRC male and female in vitro and in vivo models, mainly from preclinical studies, alongside their potential molecular mechanisms. Most of the studies showed that E2 exogenous treatment and/or reactivation of its beta receptor (ERβ) significantly inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis by modulating several molecular pathways. Likewise, the inhibition of ERα receptors produced similar antitumorigenic actions, both in vivo and in vitro, suggesting that E2 could have dual opposing roles in CRC that are dependent on the expression profile of its nuclear receptors. The available studies on P4 are scarce, and the results revealed that in vitro and in vivo treatments with natural and synthetic progesterone were also associated with promising tumoricidal actions. Nevertheless, the combination of E2 with P4 showed enhanced anticancer activities compared with their monotherapy protocols in male–female cell lines and animals. Collectively, the studies suggested that the female sex steroid hormones could provide a novel and effective therapeutic strategy against CRC.
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18
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Abstract
Background: Sex dimorphism strongly impacts tumor biology, with most cancers having a male predominance. Uniquely, thyroid cancer (TC) is the only nonreproductive cancer with striking female predominance with three- to four-fold higher incidence among females, although males generally have more aggressive disease. The molecular basis for this observation is not known, and current approaches in treatment and surveillance are not sex specific. Summary: Although TC has overall good prognosis, 6-20% of patients develop regional or distant metastasis, one third of whom are not responsive to conventional treatment approaches and suffer a 10-year survival rate of only 10%. More efficacious treatment strategies are needed for these aggressive TCs, as tyrosine kinase inhibitors and immunotherapy have major toxicities without demonstrable overall survival benefit. Emerging evidence indicates a role of sex hormones, genetics, and the immune system in modulation of both risk for TC and its progression in a sex-specific manner. Conclusion: Greater understanding of the molecular mechanisms underlying sex differences in TC pathogenesis could provide insights into the development of sex-specific, targeted, and effective strategies for prevention, diagnosis, and management. This review summarizes emerging evidence for the importance of sex in the pathogenesis, progression, and response to treatment in differentiated TC with emphasis on the role of sex hormones, genetics, and the immune system.
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Affiliation(s)
- Leila Shobab
- MedStar Washington Hospital Center, Washington, District of Columbia, USA
| | - Kenneth D Burman
- MedStar Washington Hospital Center, Washington, District of Columbia, USA
| | - Leonard Wartofsky
- Medstar Health Research Institute, Washington, District of Columbia, USA
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19
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Lasagna M, Ventura C, Hielpos MS, Mardirosian MN, Martín G, Miret N, Randi A, Núñez M, Cocca C. Endocrine disruptor chlorpyrifos promotes migration, invasion, and stemness phenotype in 3D cultures of breast cancer cells and induces a wide range of pathways involved in cancer progression. ENVIRONMENTAL RESEARCH 2022; 204:111989. [PMID: 34506784 DOI: 10.1016/j.envres.2021.111989] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 06/13/2023]
Abstract
Organophosphorus chlorpyrifos (CPF) is currently considered an endocrine disruptor (ED), as it can imitate hormone actions both in vitro and in vivo. We recently reported that CPF induces migration and invasion in 2D cultures and changes the expression of key molecular markers involved in epithelial mesenchymal transition in MCF-7 and MDA-MB-231 cell lines. In this study, we investigated whether CPF could behave as a predisposing factor for tumors to become more metastatic and aggressive using 3D culture models. In MCF-7 cells, 0.05 μM CPF induced an increase in the number and size of mammospheres via estrogen receptor alpha (ERα) and c-SRC. Furthermore, 0.05 μM CPF increased the area of spheroids generated from MCF-7 cells, induced invasion using both Matrigel® and type 1 collagen matrices, and increased cell migration capacity via ERα in this 3D model. In turn, 50 μM CPF increased cell migration capacity and invasion using type 1 collagen matrix. In monolayers, CPF increased the phosphorylation and membrane translocation of c-SRC at both concentrations assayed. CPF at 0.05 μM boosted p-AKT, p-GSK-3β and p-P38. While p-AKT rose in a ERα-dependent way, p-GSK-3β was dependent on ERα- and c-SRC, and p-P38 was only dependent on c-SRC. On the other hand, the increase in p-AKT and p-P38 induced by 50 μM CPF was dependent on the c-SRC pathway. We also observed that 0.05 μM CPF increased IGF-1R and IRS-1 expression and that 50 μM CPF induced IGF-1Rβ phosphorylation. In the MDA-MB-231 cell line, 0.05 and 50 μM CPF increased p-c-SRC. Finally, p-AKT and p-GSK-3β were also induced by CPF at 0.05 and 50 μM, and an increase in p-P38 was observed at 50 μM. Taken together, these data provide support for the notion that CPF may represent a risk factor for breast cancer development and progression.
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Affiliation(s)
- M Lasagna
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - C Ventura
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina; Universidad Nacional de La Plata-CONICET, Instituto de Estudios Inmunológicos y Fisiopatológicos (IIFP), La Plata, Argentina
| | - M S Hielpos
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - M N Mardirosian
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina
| | - G Martín
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - N Miret
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Buenos Aires, Argentina
| | - A Randi
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Buenos Aires, Argentina
| | - M Núñez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - C Cocca
- Universidad de Buenos Aires-CONICET, Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini" (IQUIFIB), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica. Cátedra de Física, Laboratorio de Radioisótopos, Buenos Aires, Argentina.
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20
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Chimento A, De Luca A, Avena P, De Amicis F, Casaburi I, Sirianni R, Pezzi V. Estrogen Receptors-Mediated Apoptosis in Hormone-Dependent Cancers. Int J Mol Sci 2022; 23:1242. [PMID: 35163166 PMCID: PMC8835409 DOI: 10.3390/ijms23031242] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERβ complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth.
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Affiliation(s)
- Adele Chimento
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Arianna De Luca
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Paola Avena
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Ivan Casaburi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Rosa Sirianni
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Vincenzo Pezzi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
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21
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Chronic exposure to nonylphenol induces oxidative stress and liver damage in male zebrafish (Danio rerio): Mechanistic insight into cellular energy sensors, lipid accumulation and immune modulation. Chem Biol Interact 2022; 351:109762. [PMID: 34843692 DOI: 10.1016/j.cbi.2021.109762] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/06/2021] [Accepted: 11/25/2021] [Indexed: 02/07/2023]
Abstract
Nonylphenol (NP), an environmentally persistent and toxic endocrine-disrupting chemical with estrogenic properties, has severe implications on humans and wildlife. Accumulating evidence demonstrates the toxic response of NP on the developmental process, nervous system, and reproductive parameters. Although NP exposure has been implicated in chronic liver injury, the underlying events associated with hepatic pathophysiology remain less investigated. Using male zebrafish (Danio rerio) as the model, the present study investigates the impact of environmentally relevant concentrations of NP (50 and 100 μg/L, 21 days) on hepatic redox homeostasis vis-à-vis cellular energy sensors, inflammatory response, and cell death involving a mechanistic insight into estrogen receptor (ER) modulation. Our results demonstrate that congruent with significant alteration in transcript abundance of antioxidant enzymes (SOD1, SOD2, Catalase, GPx1a, GSTα1), chronic exposure to NP promotes ROS synthesis, more specifically superoxide anions and H2O2 levels, and lipid peroxidation potentially through elevated NOX4 expression. Importantly, NP perturbation of markers associated with fatty acid biosynthesis (srebf1/fasn) and cellular energy-sensing network (sirt1/ampkα/pgc1α) indicates dysregulated energy homeostasis, metabolic disruption, and macrovesicular steatosis, albeit with differential sensitivity at the dose level tested. Besides, elevated p38-MAPK phosphorylation (activation) together with loss of ER homeostasis at both mRNA (esr1, esr2a, esr2b) and protein (ERα, ERβ) levels suggest that NP modulation of ER abundance may have a significant influence on hepatic events. Elevated expression of inflammatory markers (TLR4, p-NF-κB, TNF-α, IL-6, IL-1β, and NOS2) and pro-apoptotic and necrotic regulators, e.g., Bax, caspase- 8, -9 and cleaved PARP1 (50 kDa), indicate chronic inflammation and hepatotoxicity in NP-exposed males. Collectively, elevated oxidative stress, metabolic dysregulation and immune modulation may lead to chronic liver injury in organisms exposed to metabolic disrupting chemicals.
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22
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Mahbub AA, Aslam A, Elzubier ME, El-Boshy M, Abdelghany AH, Ahmad J, Idris S, Almaimani R, Alsaegh A, El-Readi MZ, Baghdadi MA, Refaat B. Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males. Front Endocrinol (Lausanne) 2022; 13:941834. [PMID: 36263327 PMCID: PMC9574067 DOI: 10.3389/fendo.2022.941834] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/14/2022] [Indexed: 12/24/2022] Open
Abstract
Although ovarian sex steroids could have protective roles against colorectal cancer (CRC) in women, little is currently known about their potential anti-tumorigenic effects in men. Hence, this study measured the therapeutic effects of 17β-oestradiol (E2) and/or progesterone (P4) against azoxymethane-induced CRC in male mice that were divided into (n = 10 mice/group): negative (NC) and positive (PC) controls, E2 (580 µg/Kg/day; five times/week) and P4 (2.9 mg/Kg/day; five times/week) monotherapies, and concurrent (EP) and sequential (E/P) co-therapy groups. Both hormones were injected intraperitoneally to the designated groups for four consecutive weeks. Similar treatment protocols with E2 (10 nM) and/or P4 (20 nM) were also used in the SW480 and SW620 human male CRC cell lines. The PC group showed abundant colonic tumours alongside increased colonic tissue testosterone levels and androgen (AR) and oestrogen (ERα) receptors, whereas E2 and P4 levels with ERβ and progesterone receptor (PGR) decreased significantly compared with the NC group. E2 and P4 monotherapies equally increased ERβ/PGR with p21/Cytochrome-C/Caspase-3, reduced testosterone levels, inhibited ERα/AR and CCND1/survivin and promoted apoptosis relative to the PC group. Both co-therapy protocols also revealed better anti-cancer effects with enhanced modulation of colonic sex steroid hormones and their receptors, with E/P the most prominent protocol. In vitro, E/P regimen showed the highest increases in the numbers of SW480 (2.1-fold) and SW620 (3.5-fold) cells in Sub-G1 phase of cell cycle. The E/P co-therapy also disclosed the lowest percentages of viable SW480 cells (2.8-fold), whilst both co-therapy protocols equally showed the greatest SW620 apoptotic cell numbers (5.2-fold) relative to untreated cells. Moreover, both co-therapy regimens revealed maximal inhibitions of cell cycle inducers, cell survival markers, and AR/ERα alongside the highest expression of cell cycle suppressors, pro-apoptotic molecules, and ERβ/PGR in both cell lines. In conclusion, CRC was associated with abnormal levels of colonic sex steroid hormones alongside aberrant protein expression of their receptors. While the anti-cancer effects of E2 and P4 monotherapies were equal, their combination protocols showed boosted tumoricidal actions against CRC in males, possibly by promoting ERβ and PGR-mediated androgen deprivation together with inhibition of ERα-regulated oncogenic pathways.
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Affiliation(s)
- Amani A. Mahbub
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mohamed E. Elzubier
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
- Biochemistry Department, Faculty of Medicine and Surgery, National University, Khartoum, Sudan
| | - Mohamed El-Boshy
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Clinical Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Abdelghany H. Abdelghany
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Riyad Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Aiman Alsaegh
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mahmoud Zaki El-Readi
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit, Egypt
| | - Mohammed A. Baghdadi
- Research Centre, King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
- *Correspondence: Bassem Refaat, ;
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23
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Acconcia F, Fiocchetti M, Busonero C, Fernandez VS, Montalesi E, Cipolletti M, Pallottini V, Marino M. The extra-nuclear interactome of the estrogen receptors: implications for physiological functions. Mol Cell Endocrinol 2021; 538:111452. [PMID: 34500041 DOI: 10.1016/j.mce.2021.111452] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 08/19/2021] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Over the last decades, a great body of evidence has defined a novel view of the cellular mechanism of action of the steroid hormone 17β-estradiol (E2) through its estrogen receptors (i.e., ERα and ERβ). It is now clear that the E2-activated ERs work both as transcription factors and extra-nuclear plasma membrane-localized receptors. The activation of a plethora of signal transduction cascades follows the E2-dependent engagement of plasma membrane-localized ERs and is required for the coordination of gene expression, which ultimately controls the occurrence of the pleiotropic effects of E2. The definition of the molecular mechanisms by which the ERs locate at the cell surface (i.e., palmitoylation and protein association) determined the quest for understanding the specificity of the extra-nuclear E2 signaling. The use of mice models lacking the plasma membrane ERα localization unveiled that the extra-nuclear E2 signaling is operational in vivo but tissue-specific. However, the underlying molecular details for such ERs signaling diversity in the perspective of the E2 physiological functions in the different cellular contexts are still not understood. Therefore, to gain insights into the tissue specificity of the extra-nuclear E2 signaling to physiological functions, here we reviewed the known ERs extra-nuclear interactors and tried to extrapolate from available databases the ERα and ERβ extra-nuclear interactomes. Based on literature data, it is possible to conclude that by specifically binding to extra-nuclear localized proteins in different sub-cellular compartments, the ERs fine-tune their molecular activities. Moreover, we report that the context-dependent diversity of the ERs-mediated extra-nuclear E2 actions can be ascribed to the great flexibility of the physical structures of ERs and the spatial-temporal organization of the logistics of the cells (i.e., the endocytic compartments). Finally, we provide lists of proteins belonging to the potential ERα and ERβ extra-nuclear interactomes and propose that the systematic experimental definition of the ERs extra-nuclear interactomes in different tissues represents the next step for the research in the ERs field. Such characterization will be fundamental for the identification of novel druggable targets for the innovative treatment of ERs-related diseases.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
| | - Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Claudia Busonero
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Virginia Solar Fernandez
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Emiliano Montalesi
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Valentina Pallottini
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences, and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
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24
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Estrogen Receptors in Colorectal Cancer: Facts, Novelties and Perspectives. Curr Oncol 2021; 28:4256-4263. [PMID: 34898546 PMCID: PMC8544350 DOI: 10.3390/curroncol28060361] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is the second cause of cancer-related death in both sexes worldwide. As pre-menopausal women are less likely to develop CRC compared to age-matched men, a protective role for estrogens has been hypothesized. Indeed, two isoforms of nuclear estrogen receptors (ER) have been described: ERα and ERβ. While the binding of 17beta-estradiol to ERα activates anti-apoptotic pathways, the interaction with ERβ activates caspase-3, inducing apoptosis. In this regard, several pieces of evidence show that ERβ tends to be under-regulated in advanced adenomas and CRC, with an opposite trend for ERα. Furthermore, ERβ stimulation slows adenomatous polyp growth and modulates relevant CRC pathways. Based on such considerations, dietary modulation of ER is promising, particularly in subjects with genetic predisposition for CRC. Nevertheless, the main limitation is the lack of clinical trials on a large population scale.
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25
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Takahashi M, Takeda J, Haneda S, Ishii S, Shinohara M, Yoshida E, Sato A, Makino S, Itakura A. "Step-by-Step" Minimally Invasive Hemostatic Technique Using Intrauterine Double-Balloon Tamponade Combined with Uterine Isthmus Vertical Compression Suture for the Control of Placenta Accreta and Severe Atonic Hemorrhage during a Cesarean Section. Surg J (N Y) 2021; 7:e216-e221. [PMID: 34466659 PMCID: PMC8390297 DOI: 10.1055/s-0041-1733990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 06/28/2021] [Indexed: 11/30/2022] Open
Abstract
A sudden onset of postpartum hemorrhage (PPH) during a cesarean delivery requires urgent hemostasis procedures, such as the B-Lynch, Hayman, or double-vertical compression sutures, when bimanual compression, uterotonic agent administration, and intrauterine balloon tamponade had failed to achieve sufficient hemostasis. However, after invasive hemostatic procedures, postoperative complications, including subsequent synechiae and infection followed by ischemia, have been reported to occur even in successful cases. To avoid these complications, we devised and performed a minimally invasive combined technique based on a “step-by-step” minimally invasive hemostatic protocol for a case of placenta accreta and severe atonic hemorrhage during a cesarean delivery. A nullipara woman with a history of systemic lupus erythematosus and treatment with prednisolone and tacrolimus underwent a cesarean section because of a nonreassuring fetal status. Severe atonic hemorrhage and placenta accreta were observed which did not respond to bimanual compression and uterotonics. Because severe uterine atony and continuous bleeding from the placental attachment area were observed even with intrauterine balloon tamponade, vertical compression sutures were placed in the uterine isthmus. However, severe uterine atony and atonic bleeding from the uterine corpus persisted; thus, a second balloon was inserted into the uterine corpus. Hemostasis was accomplished with a combination of isthmus vertical compression sutures and double balloons which is a less-invasive approach than existing compression techniques. No complications related to these procedures were observed. This step-by-step minimally invasive hemostatic technique has the potential to control PPH with less complications, especially in immunocompromised patients.
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Affiliation(s)
- Masaya Takahashi
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Jun Takeda
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Sumie Haneda
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Sumire Ishii
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Mitsuko Shinohara
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Emiko Yoshida
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Anna Sato
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Shintaro Makino
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Atsuo Itakura
- Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan
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26
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Solar Fernandez V, Fiocchetti M, Cipolletti M, Segatto M, Cercola P, Massari A, Ghinassi S, Cavaliere F, Marino M. Neuroglobin: A New Possible Marker of Estrogen-Responsive Breast Cancer. Cells 2021; 10:cells10081986. [PMID: 34440755 PMCID: PMC8393432 DOI: 10.3390/cells10081986] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/30/2021] [Accepted: 08/04/2021] [Indexed: 01/27/2023] Open
Abstract
The expression of the α-subtype of Estrogen Receptor (ERα) characterizes most breast cancers (more than 75%), for which endocrine therapy is the mainstay for their treatment. However, a high percentage of ERα+ breast cancers are de novo or acquired resistance to endocrine therapy, and the definition of new targets for improving therapeutic interventions and the prediction of treatment response is demanding. Our previous data identified the ERα/AKT/neuroglobin (NGB) pathway as a common pro-survival process activated in different ERα breast cancer cell lines. However, no in vivo association between the globin and the malignity of breast cancer has yet been done. Here, we evaluated the levels and localization of NGB in ERα+ breast ductal carcinoma tissue of different grades derived from pre-and post-menopausal patients. The results indicate a strong association between NGB accumulation, ERα, AKT activation, and the G3 grade, while no association with the menopausal state has been evidenced. Analyses of the data set (e.g., GOBO) strengthen the idea that NGB accumulation could be linked to tumor cell aggressiveness (high grade) and resistance to treatment. These data support the view that NGB accumulation, mainly related to ER expression and tumor grade, represents a compensatory process, which allows cancer cells to survive in an unfavorable environment.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/analysis
- Breast Neoplasms/chemistry
- Breast Neoplasms/mortality
- Breast Neoplasms/pathology
- Breast Neoplasms/therapy
- Carcinoma, Ductal, Breast/chemistry
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/therapy
- Case-Control Studies
- Disease Progression
- Estrogen Receptor alpha/analysis
- Female
- Humans
- Immunohistochemistry
- Middle Aged
- Neoplasm Grading
- Neuroglobin/analysis
- Progression-Free Survival
- Proto-Oncogene Proteins c-akt/analysis
- Signal Transduction
- Tumor Microenvironment
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Affiliation(s)
- Virginia Solar Fernandez
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (M.C.)
| | - Marco Fiocchetti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (M.C.)
- Correspondence: (M.F.); (M.M.); Tel.: +39-06-5733-6455 (M.F.); +39-06-5733-6320 (M.M.); Fax: +39-06-5733-6321 (M.F. & M.M.)
| | - Manuela Cipolletti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (M.C.)
| | - Marco Segatto
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche (IS), Italy;
| | - Paolo Cercola
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (S.G.); (F.C.)
| | - Annalisa Massari
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (S.G.); (F.C.)
| | - Sabrina Ghinassi
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (S.G.); (F.C.)
| | - Francesco Cavaliere
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (S.G.); (F.C.)
| | - Maria Marino
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (M.C.)
- Correspondence: (M.F.); (M.M.); Tel.: +39-06-5733-6455 (M.F.); +39-06-5733-6320 (M.M.); Fax: +39-06-5733-6321 (M.F. & M.M.)
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27
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Cervantes-Candelas LA, Aguilar-Castro J, Buendía-González FO, Fernández-Rivera O, Cervantes-Sandoval A, Morales-Montor J, Legorreta-Herrera M. Tamoxifen Suppresses the Immune Response to Plasmodium berghei ANKA and Exacerbates Symptomatology. Pathogens 2021; 10:pathogens10060743. [PMID: 34204678 PMCID: PMC8231265 DOI: 10.3390/pathogens10060743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/04/2021] [Accepted: 06/09/2021] [Indexed: 12/25/2022] Open
Abstract
Malaria is the most lethal parasitic disease in the world. Mortality and severity in symptoms are higher in men than women, suggesting that oestrogens, which are in higher concentration in females than in males, may regulate the immune response against malaria. Tamoxifen, a selective oestrogen receptor modulator used in breast cancer treatment due to its antagonistic effect on oestrogen receptors α and β, is also studied because of its potential therapeutic use for several parasitic diseases. However, most studies, including one in malaria, have not addressed the immunomodulatory role of tamoxifen. In this work, we evaluated the effect of tamoxifen on the immune response of CBA/Ca mice against Plasmodium berghei ANKA. This study showed for the first time that tamoxifen increased parasite load, aggravated symptoms by decreasing body temperature and body weight, and worsened anaemia. Additionally, tamoxifen significantly increased the splenic index and the percentages of CD4+ and NK+ cells on day eight post-infection. By contrast, tamoxifen decreased both CD8+ and B220+ populations in the spleen and decreased the serum levels of IL-2, IL-6, and IL-17. Our findings support the notion that tamoxifen is a potent immunomodulator in malaria-infected mice and suggest caution when administering it to malaria-infected women with breast cancer.
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Affiliation(s)
- Luis Antonio Cervantes-Candelas
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico, Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.A.C.-C.); (J.A.-C.); (F.O.B.-G.); (O.F.-R.)
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Edificio D, 1° Piso, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, Ciudad de México 04510, Mexico
| | - Jesús Aguilar-Castro
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico, Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.A.C.-C.); (J.A.-C.); (F.O.B.-G.); (O.F.-R.)
| | - Fidel Orlando Buendía-González
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico, Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.A.C.-C.); (J.A.-C.); (F.O.B.-G.); (O.F.-R.)
| | - Omar Fernández-Rivera
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico, Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.A.C.-C.); (J.A.-C.); (F.O.B.-G.); (O.F.-R.)
| | - Armando Cervantes-Sandoval
- Laboratorio de Aplicaciones Computacionales, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico;
| | - Jorge Morales-Montor
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, AP 70228, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico;
| | - Martha Legorreta-Herrera
- Unidad de Investigación Química Computacional, Síntesis y Farmacología de Moléculas de Interés Biológico, Laboratorio de Inmunología Molecular, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, Ciudad de México 09230, Mexico; (L.A.C.-C.); (J.A.-C.); (F.O.B.-G.); (O.F.-R.)
- Correspondence: ; Tel.: +52-5556230700 (ext. 83207)
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Niță AR, Knock GA, Heads RJ. Signalling mechanisms in the cardiovascular protective effects of estrogen: With a focus on rapid/membrane signalling. Curr Res Physiol 2021; 4:103-118. [PMID: 34746830 PMCID: PMC8562205 DOI: 10.1016/j.crphys.2021.03.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/22/2022] Open
Abstract
In modern society, cardiovascular disease remains the biggest single threat to life, being responsible for approximately one third of worldwide deaths. Male prevalence is significantly higher than that of women until after menopause, when the prevalence of CVD increases in females until it eventually exceeds that of men. Because of the coincidence of CVD prevalence increasing after menopause, the role of estrogen in the cardiovascular system has been intensively researched during the past two decades in vitro, in vivo and in observational studies. Most of these studies suggested that endogenous estrogen confers cardiovascular protective and anti-inflammatory effects. However, clinical studies of the cardioprotective effects of hormone replacement therapies (HRT) not only failed to produce proof of protective effects, but also revealed the potential harm estrogen could cause. The "critical window of hormone therapy" hypothesis affirms that the moment of its administration is essential for positive treatment outcomes, pre-menopause (3-5 years before menopause) and immediately post menopause being thought to be the most appropriate time for intervention. Since many of the cardioprotective effects of estrogen signaling are mediated by effects on the vasculature, this review aims to discuss the effects of estrogen on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) with a focus on the role of estrogen receptors (ERα, ERβ and GPER) in triggering the more recently discovered rapid, or membrane delimited (non-genomic), signaling cascades that are vital for regulating vascular tone, preventing hypertension and other cardiovascular diseases.
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Affiliation(s)
- Ana-Roberta Niță
- School of Bioscience Education, Faculty of Life Sciences and Medicine, King’s College London, UK
| | - Greg A. Knock
- School of Bioscience Education, Faculty of Life Sciences and Medicine, King’s College London, UK
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK
| | - Richard J. Heads
- School of Bioscience Education, Faculty of Life Sciences and Medicine, King’s College London, UK
- Cardiovascular Research Section, King’s BHF Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, Faculty of Life Sciences and Medicine, King’s College London, UK
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A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms22062915. [PMID: 33805656 PMCID: PMC8000495 DOI: 10.3390/ijms22062915] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/09/2021] [Accepted: 03/11/2021] [Indexed: 12/22/2022] Open
Abstract
17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.
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Božović A, Mandušić V, Todorović L, Krajnović M. Estrogen Receptor Beta: The Promising Biomarker and Potential Target in Metastases. Int J Mol Sci 2021; 22:ijms22041656. [PMID: 33562134 PMCID: PMC7914503 DOI: 10.3390/ijms22041656] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/24/2020] [Accepted: 01/15/2021] [Indexed: 12/21/2022] Open
Abstract
The discovery of the Estrogen Receptor Beta (ERβ) in 1996 opened new perspectives in the diagnostics and therapy of different types of cancer. Here, we present a review of the present research knowledge about its role in endocrine-related cancers: breast, prostate, and thyroid, and colorectal cancers. We also discuss the reasons for the controversy of its role in carcinogenesis and why it is still not in use as a biomarker in clinical practice. Given that the diagnostics and therapy would benefit from the introduction of new biomarkers, we suggest ways to overcome the contradictions in elucidating the role of ERβ.
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Ciccone L, Nencetti S, Socci S, Orlandini E. Neuroglobin and neuroprotection: the role of natural and synthetic compounds in neuroglobin pharmacological induction. Neural Regen Res 2021; 16:2353-2358. [PMID: 33907006 PMCID: PMC8374583 DOI: 10.4103/1673-5374.300981] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Neuroglobin (Ngb) is a 17 kDa monomeric hexa-coordinated heme protein belonging to the globin family. Ngb is mainly expressed in neurons of the central and peripheral nervous system, although moderate levels of Ngb have been detected in non-nervous tissues. In the past decade, Ngb has been studied for its neuroprotective role in a large number of neurological disorders such as Alzheimer's disease, Huntington's disease, brain ischemia and hypoxia. This review discusses and summarizes the natural compounds and the small synthetic molecules capable of modulating Ngb expression that exhibits a protective role against various neurodegenerative diseases.
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Affiliation(s)
- Lidia Ciccone
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | | | - Simone Socci
- Department of Earth Sciences, University of Pisa, Pisa, Italy
| | - Elisabetta Orlandini
- Department of Earth Sciences, University of Pisa; Research Center "E. Piaggio," University of Pisa, Pisa, Italy
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Ban WW, Lee YJ, Lee SH, Jung JY, Baek BJ. Expression of Estrogen Receptor-alpha in Nasal Polyps and the Effects of Dexamethasone on Estrogen Receptor-alpha Expression in RPMI 2650 Cells. J Korean Med Sci 2020; 35:e420. [PMID: 33372422 PMCID: PMC7769702 DOI: 10.3346/jkms.2020.35.e420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 11/01/2020] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Studies have reported that epithelial cell proliferation may be involved in the pathogenesis of nasal polyps (NPs). Estrogen receptor (ER)-α, one type of ER, is related to anti-inflammatory action and cell survival in certain tissues. In this study, we examined the presence or absence of ER-α in NPs and healthy inferior turbinate mucosae. We also investigated the effect of dexamethasone on ER-α expression, cell viability, and apoptosis in RPMI 2650 cells. METHODS Immunohistochemical staining and Western blot analysis were conducted to determine the expression of ER-α in 15 NPs and 15 healthy inferior turbinate mucosae. After treating RPMI 2650 cells with dexamethasone, ER-α expression was analyzed using Western blot analysis and cell viability was determined using the MTT assay. Western blot analysis and annexin V-phycoerythrin (PE) staining were used to examine apoptotic cell death. RESULTS Western blot analysis showed that ER-α expression was upregulated in 13 of the 15 NP tissues. Immunohistochemical staining for ER-α confirmed the results of the Western blot analysis. When RPMI 2650 cells were treated with dexamethasone, both ER-α expression and cell viability were decreased. Furthermore, the treatment of RPMI 2650 cells with dexamethasone increased apoptotic cell death, as shown by increased levels of BAX and cleaved caspase-3, decreased levels of Bcl-2, and an increased percentage of positive annexin V-PE stained cells. CONCLUSION ER-α expression was higher in NPs than in healthy inferior turbinate mucosae. When RPMI 2650 cells were treated with dexamethasone, ER-α expression was downregulated, cell viability decreased, and apoptosis increased. The decreased cell viability may be related, at least in part, to the decreased ER-α protein levels, which likely contributed to the induction of apoptotic cell death in RPMI 2650 cells.
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Affiliation(s)
- Won Woo Ban
- Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Yoon Jin Lee
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sang Han Lee
- Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jae Yeop Jung
- Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Byoung Joon Baek
- Department of Otorhinolaryngology-Head and Neck Surgery, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea.
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33
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Inoue A, Horinouchi T, Yoshizato T, Kojiro-Sanada S, Kozuma Y, Ushijima K. Peculiar blood flow profiles among placental chorionic villous vessels of an abnormally thick placenta in a case of systemic lupus erythematosus characterized using microvascular imaging. J Obstet Gynaecol Res 2020; 46:2684-2690. [PMID: 33047457 DOI: 10.1111/jog.14502] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/26/2020] [Accepted: 08/30/2020] [Indexed: 02/03/2023]
Abstract
We present a patient with systemic lupus erythematosus receiving long-term steroid therapy, who had myometrial thinning, markedly thickened placenta, and fetal growth restriction (FGR). Blood flow profiles of the myometrium, decidua and placental villous vessels (VV) were described using superb microvascular imaging (SMI) at 35 weeks' gestation. Images showed no decidual blood flow underneath the placenta sitting on a thin myometrium and sparse VV distribution and non-visualization of peripheral VV flow. Emergency cesarean hysterectomy was performed at 36 weeks. Histological findings showed missing decidua on the thin myometrium, which indicated placenta accreta spectrum, and massive perivillous fibrin deposition and increased numbers of syncytial knots in the placenta. We speculated that the thick placenta and peculiar VV flow profiles resulted from congestion of the intervillous space and intervillous underperfusion/low intraplacental oxygenation, respectively, resulting in FGR. Superb microvascular imaging is useful for diagnosing placenta accreta spectrum and understanding the pathophysiology of thick placenta and FGR.
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Affiliation(s)
- Asami Inoue
- Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan
| | - Takashi Horinouchi
- Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan
| | - Toshiyuki Yoshizato
- Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan
| | | | - Yutaka Kozuma
- Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan
| | - Kimio Ushijima
- Department of Obstetrics and Gynecology, School of Medicine, Kurume University, Kurume, Japan
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Mal R, Magner A, David J, Datta J, Vallabhaneni M, Kassem M, Manouchehri J, Willingham N, Stover D, Vandeusen J, Sardesai S, Williams N, Wesolowski R, Lustberg M, Ganju RK, Ramaswamy B, Cherian MA. Estrogen Receptor Beta (ERβ): A Ligand Activated Tumor Suppressor. Front Oncol 2020; 10:587386. [PMID: 33194742 PMCID: PMC7645238 DOI: 10.3389/fonc.2020.587386] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) belong to a superfamily of nuclear receptors called steroid hormone receptors, which, upon binding ligand, dimerize and translocate to the nucleus where they activate or repress the transcription of a large number of genes, thus modulating critical physiologic processes. ERβ has multiple isoforms that show differing association with prognosis. Expression levels of the full length ERβ1 isoform are often lower in aggressive cancers as compared to normal tissue. High ERβ1 expression is associated with improved overall survival in women with breast cancer. The promise of ERβ activation, as a potential targeted therapy, is based on concurrent activation of multiple tumor suppressor pathways with few side effects compared to chemotherapy. Thus, ERβ is a nuclear receptor with broad-spectrum tumor suppressor activity, which could serve as a potential treatment target in a variety of human cancers including breast cancer. Further development of highly selective agonists that lack ERα agonist activity, will be necessary to fully harness the potential of ERβ.
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Affiliation(s)
- Rahul Mal
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Alexa Magner
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Joel David
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Jharna Datta
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Meghna Vallabhaneni
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Mahmoud Kassem
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Jasmine Manouchehri
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Natalie Willingham
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Daniel Stover
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Jeffery Vandeusen
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Sagar Sardesai
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Nicole Williams
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Robert Wesolowski
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Maryam Lustberg
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Ramesh K Ganju
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
| | - Bhuvaneswari Ramaswamy
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
| | - Mathew A Cherian
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.,Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, United States
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35
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Fiocchetti M, Solar Fernandez V, Segatto M, Leone S, Cercola P, Massari A, Cavaliere F, Marino M. Extracellular Neuroglobin as a Stress-Induced Factor Activating Pre-Adaptation Mechanisms against Oxidative Stress and Chemotherapy-Induced Cell Death in Breast Cancer. Cancers (Basel) 2020; 12:cancers12092451. [PMID: 32872414 PMCID: PMC7564643 DOI: 10.3390/cancers12092451] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 08/26/2020] [Indexed: 12/16/2022] Open
Abstract
Components of tumor microenvironment, including tumor and/or stromal cells-derived factors, exert a critical role in breast cancer (BC) progression. Here we evaluated the possible role of neuroglobin (NGB), a monomeric globin that acts as a compensatory protein against oxidative and apoptotic processes, as part of BC microenvironment. The extracellular NGB levels were evaluated by immunofluorescence of BC tissue sections and by Western blot of the culture media of BC cell lines. Moreover, reactive oxygen species (ROS) generation, cell apoptosis, and cell migration were evaluated in different BC cells and non-tumorigenic epithelial mammary cells treated with BC cells (i.e., Michigan Cancer Foundation-7, MCF-7) conditioned culture media and extracellular NGB. Results demonstrate that NGB is a component of BC microenvironment. NGB is released in tumor microenvironment by BC cells only under oxidative stress conditions where it can act as autocrine/paracrine factor able to communicate cell resilience against oxidative stress and chemotherapeutic treatment.
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Affiliation(s)
- Marco Fiocchetti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (S.L.)
- Correspondence: (M.F.); (M.M.); Tel.: +39-06-5733-6455 (M.F.); +39-06-5733-6320 (M.M.); Fax: +39-06-5733-6321 (M.F. & M.M.)
| | - Virginia Solar Fernandez
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (S.L.)
| | - Marco Segatto
- Department of Biosciences and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche (IS), Italy;
| | - Stefano Leone
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (S.L.)
| | - Paolo Cercola
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (F.C.)
| | - Annalisa Massari
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (F.C.)
| | - Francesco Cavaliere
- Division of Senology, Belcolle Hospital, Str. Sammartinese, 01100 Viterbo, Italy; (P.C.); (A.M.); (F.C.)
| | - Maria Marino
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy; (V.S.F.); (S.L.)
- Correspondence: (M.F.); (M.M.); Tel.: +39-06-5733-6455 (M.F.); +39-06-5733-6320 (M.M.); Fax: +39-06-5733-6321 (M.F. & M.M.)
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Maingi JW, Tang S, Liu S, Ngenya W, Bao E. Targeting estrogen receptors in colorectal cancer. Mol Biol Rep 2020; 47:4087-4091. [PMID: 32246248 DOI: 10.1007/s11033-020-05414-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/28/2020] [Indexed: 02/06/2023]
Abstract
Hormones have become a useful therapeutic aspect of clinical endocrinology but how to use them to optimize the health benefits and avoid adverse effects is a major challenge. Estrogen is an indispensable hormone for proper biological functioning but is also implicated with the pathology of both the reproductive and non-reproductive tissues. Abnormal estrogen receptor signaling may increase the risk of development of a variety of diseases including colorectal cancer (CRC). Estrogen receptor beta (ERβ) is the predominant subtype in the colonic epithelium and confers the anti-tumor effect through various mechanisms. Many investigators have embarked on the search for the biological mechanisms by which estrogen and estrogen-like compounds may influence the pathogenesis of CRC. This review explores the recent findings on the therapeutic role of ERβ in the colonic epithelium as a prospective candidate for targeted endocrine therapy in CRC.
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Affiliation(s)
- Joyce Wanjiru Maingi
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, China.
| | - Shu Tang
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, China
| | - Sirui Liu
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, China
| | - Watson Ngenya
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, China
| | - Endong Bao
- College of Veterinary Medicine, Nanjing Agricultural University, Weigang 1, Nanjing, 210095, China
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Liu Y, Ma H, Yao J. ERα, A Key Target for Cancer Therapy: A Review. Onco Targets Ther 2020; 13:2183-2191. [PMID: 32210584 PMCID: PMC7073439 DOI: 10.2147/ott.s236532] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 02/20/2020] [Indexed: 12/18/2022] Open
Abstract
Estrogen receptor α (ERα) is closely associated with both hormone-dependent and hormone-independent tumors, and it is also essential for the development of these cancers. The functions of ERα are bi-faceted; it can contribute to cancer progression as well as cancer inhibition. Therefore, understanding ERα is vital for the treatment of those cancers that are closely associated with its expression. Here, we will elaborate on ERα based on its structure, localization, activation, modification, and mutation. Also, we will look at co-activators of ERα, elucidate the signaling pathway activated by ERα, and identify cancers related to its activation. A comprehensive understanding of ERα could help us to find new ways to treat cancers.
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Affiliation(s)
- Yanfang Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Hong Ma
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
| | - Jing Yao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, People's Republic of China
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Quercetin promotes the survival of granulocytic myeloid-derived suppressor cells via the ESR2/STAT3 signaling pathway. Biomed Pharmacother 2020; 125:109922. [PMID: 32007919 DOI: 10.1016/j.biopha.2020.109922] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/09/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023] Open
Abstract
Quercetin is a natural product that has been shown to induce tumor apoptosis and necrosis through multiple mechanisms. Tumor-induced myeloid-derived suppressor cell (MDSC) expansion negatively regulates the immune response by inhibiting T cell function through signal transducer and activator of transcription 3 (STAT3) activation, thereby facilitating tumor escape from host immune surveillance. Thus MDSC is an attractive target for cancer immunotherapy to enhance cytotoxic T cell responses. However, the effects of quercetin on MDSC are poorly understood. Here, we demonstrate that quercetin treatment enhanced mouse- and human- derived granulocytic-myeloid-derived suppressor cells (G-MDSC) survival and promoted the secretion of T cell-suppressive factors in vitro. Bioinformatics analysis further showed that quercetin was highly correlated with the estrogen receptor signaling pathway, which was confirmed by quantitative reverse transcription-polymerase chain reaction and flow cytometric analysis. These findings highlight the potential advantages and feasibility of quercetin in reinforcing the suppressive property of G-MDSC. Thus impact of G-MDSC should be taken into consideration when quercetin is applied to tumor therapy.
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39
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Cipolletti M, Leone S, Bartoloni S, Busonero C, Acconcia F. Real-time measurement of E2: ERα transcriptional activity in living cells. J Cell Physiol 2020; 235:6697-6710. [PMID: 31989654 DOI: 10.1002/jcp.29565] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022]
Abstract
Kinetic analyses of diverse physiological processes have the potential to unveil new aspects of the molecular regulation of cell biology at temporal levels. 17β-estradiol (E2) regulates diverse physiological effects by binding to the estrogen receptor α (ERα), which primarily works as a transcription factor. Although many molecular details of the modulation of ERα transcriptional activity have been discovered including the impact of receptor plasma membrane localization and its relative E2-evoked signaling, the knowledge of real-time ERα transcriptional dynamics in living cells is lacking. Here, we report the generation of MCF-7 and HeLa cells stably expressing a modified luciferase under the control of an E2-sensitive promoter, which activity can be continuously monitored in living cells and show that E2 induces a linear increase in ERα transcriptional activity. Ligand-independent (e.g., epidermal growth factor) receptor activation was also detected in a time-dependent manner. Kinetic profiles of ERα transcriptional activity measured in the presence of both receptor antagonists and inhibitors of ERα plasma membrane localization reveal a biphasic dynamic of receptor behavior underlying novel aspects of receptor-regulated transcriptional effects. Finally, analysis of the rate of the dose-dependent E2 induction of ERα transcriptional activity demonstrates that low doses of E2 induce an effect identical to that determined by high concentrations of E2 as a function of the duration of hormone administration. Overall, we present the characterization of sensitive stable cell lines were to study the kinetic of E2 transcriptional signaling and to identify new aspects of ERα function in different physiological or pathophysiological conditions.
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Affiliation(s)
- Manuela Cipolletti
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Stefano Leone
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Stefania Bartoloni
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Claudia Busonero
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
| | - Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Rome, Italy
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40
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Ishihara Y, Sakurai H, Oguro A, Tsuji M, Vogel CFA, Yamazaki T. Retinoid X receptor-mediated neuroprotection via CYP19 upregulation and subsequent increases in estradiol synthesis. J Steroid Biochem Mol Biol 2019; 193:105421. [PMID: 31265900 DOI: 10.1016/j.jsbmb.2019.105421] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/14/2019] [Accepted: 06/28/2019] [Indexed: 10/26/2022]
Abstract
Increasing evidence has shown that one of the major neurosteroids, estradiol, has potent neuroprotective actions. We have reported that estradiol synthesis was enhanced when retinoic acid was added into rat hippocampal slice culture. In this study, we investigated the effects of a potent retinoid X receptor (RXR) agonist, bexarotene, on estrogen synthesis and neuroprotective action in hippocampal slices. Treatment with bexarotene increased estradiol levels as well as estrogen-synthesizing enzymes and CYP19 expression in hippocampal slice cultures. Bexarotene significantly suppressed neuronal cell death induced by oxygen-glucose deprivation (OGD)/reoxygenation. RXR agonists other than bexarotene, such as CD3254, also suppressed neuronal cell death accompanied by OGD/reoxygenation. The RXR antagonists HX531 and UVI3003 and the CYP19 inhibitor letrozole abolished the neuroprotection elicited by bexarotene, indicating that estradiol produced by RXR stimulation protects neurons from ischemic insult. The human brain-specific CYP19 promoter had 6 RXR half sites, and 2 of 6 half sites were responsible for CYP19 expression induced by bexarotene. Bexarotene increased the expression of catalase and glutathione peroxidase 1 and inhibited lipid peroxidation elicited by OGD/reoxygenation, suggesting that the antioxidative property of estrogen contributes to RXR-mediated neuroprotection. Bexarotene also suppressed neuronal injury induced by lipopolysaccharide in the hippocampal slices. Taken together, RXR stimulation can protect neurons via enhanced synthesis of estradiol with antioxidative mechanisms. The RXR-estrogen axis might be a novel mechanism-based strategy to prevent or ameliorate ischemic and/or inflammatory neuronal disorders.
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Affiliation(s)
- Yasuhiro Ishihara
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan; Center for Health and the Environment, University of California, Davis, CA, 95616, USA.
| | - Hikaru Sakurai
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan
| | - Ami Oguro
- Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan
| | - Mayumi Tsuji
- Department of Environmental Health, University of Occupational and Environmental Health, Fukuoka 807-8555, Japan
| | - Christoph F A Vogel
- Center for Health and the Environment, University of California, Davis, CA, 95616, USA; Department of Environmental Toxicology, University of California, Davis, CA, 95616, USA
| | - Takeshi Yamazaki
- Program of Life and Environmental Sciences, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima 739-8521, Japan
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Chu DT, Phuong TNT, Tien NLB, Tran DK, Nguyen TT, Thanh VV, Quang TL, Minh LB, Pham VH, Ngoc VTN, Kushekhar K, Chu-Dinh T. The Effects of Adipocytes on the Regulation of Breast Cancer in the Tumor Microenvironment: An Update. Cells 2019; 8:E857. [PMID: 31398937 PMCID: PMC6721665 DOI: 10.3390/cells8080857] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/27/2019] [Accepted: 08/06/2019] [Indexed: 12/24/2022] Open
Abstract
Obesity is a global pandemic and it is well evident that obesity is associated with the development of many disorders including many cancer types. Breast cancer is one of that associated with a high mortality rate. Adipocytes, a major cellular component in adipose tissue, are dysfunctional during obesity and also known to promote breast cancer development both in vitro and in vivo. Dysfunctional adipocytes can release metabolic substrates, adipokines, and cytokines, which promote proliferation, progression, invasion, and migration of breast cancer cells. The secretion of adipocytes can alter gene expression profile, induce inflammation and hypoxia, as well as inhibit apoptosis. It is known that excessive free fatty acids, cholesterol, triglycerides, hormones, leptin, interleukins, and chemokines upregulate breast cancer development. Interestingly, adiponectin is the only adipokine that has anti-tumor properties. Moreover, adipocytes are also related to chemotherapeutic resistance, resulting in the poorer outcome of treatment and advanced stages in breast cancer. Evaluation of the adipocyte secretion levels in the circulation can be useful for prognosis and evaluation of the effectiveness of cancer therapy in the patients. Therefore, understanding about functions of adipocytes as well as obesity in breast cancer may reveal novel targets that support the development of new anti-tumor therapy. In this systemic review, we summarize and update the effects of secreted factors by adipocytes on the regulation of breast cancer in the tumor microenvironment.
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Affiliation(s)
- Dinh-Toi Chu
- Faculty of Biology, Hanoi National University of Education, Hanoi 100000, Vietnam.
- School of Odonto Stomatology, Hanoi Medical University, Hanoi 100000, Vietnam.
- Former address: Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, 0349 Oslo, Norway.
| | - Thuy Nguyen Thi Phuong
- Department of Animal Science, College of Agriculture and Life Science, Chonnam National University, Gwangju 61186, Korea
| | - Nguyen Le Bao Tien
- Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi 100000, Vietnam
| | - Dang-Khoa Tran
- Department of Anatomy, University of Medicine Pham Ngoc Thach, Ho Chi Minh City 700000, Vietnam
| | - Tran-Thuy Nguyen
- Department of Cardiovascular and Thoracic Surgery, Cardiovascular Center, E Hospital, Hanoi 100000, Vietnam
- School of Medicine and Pharmacy, Vietnam National University, Hanoi 100000, Vietnam
| | - Vo Van Thanh
- Institute of Orthopaedics and Trauma Surgery, Viet Duc Hospital, Hanoi 100000, Vietnam
- Department of Surgery, Hanoi Medical University, Hanoi 100000, Vietnam
| | - Thuy Luu Quang
- Center for Anesthesia and Surgical Intensive Care, Viet Duc Hospital, Hanoi 100000, Vietnam
| | - Le Bui Minh
- NTT Hi-tech Institute, Nguyen Tat Thanh University, 300A Nguyen Tat Thanh St., Ward 13, District 4, Ho Chi Minh City 700000, Vietnam
| | - Van Huy Pham
- AI Lab, Faculty of Information Technology, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam.
| | - Vo Truong Nhu Ngoc
- School of Odonto Stomatology, Hanoi Medical University, Hanoi 100000, Vietnam
| | - Kushi Kushekhar
- Institute of Cancer Research, Oslo University Hospital, 0310 Oslo, Norway
| | - Thien Chu-Dinh
- Institute for Research and Development, Duy Tan University, Danang 550000, Vietnam.
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Wei Y, Huang J. Role of estrogen and its receptors mediated-autophagy in cell fate and human diseases. J Steroid Biochem Mol Biol 2019; 191:105380. [PMID: 31078693 DOI: 10.1016/j.jsbmb.2019.105380] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 12/11/2022]
Abstract
Studies have shown that morbidity of several diseases varies between males and females. This difference likely arises due to sex-related hormones. Estrogen, a primary female sex steroid hormone, plays a critical role in mediating many of the physiological functions like growth, differentiation, metabolism, and cell death. Recently, it has been demonstrated that estrogen mediates autophagy through its receptors (ERs) namely ERα, ERβ, and G-protein coupled estrogen receptor (GPER). However, the specific role of estrogen and its receptors mediated-autophagy in cell fate and human diseases such as cancers, cardiovascular disease and nervous system disease remains unclear. In this review, we comprehensively summarize the complex role of estrogen and its receptors-mediated autophagy in different cell lines and human diseases. In addition, we further discuss the key signaling molecules governing the role of ERs in autophagy. This review will serve as the basis for a proposed model of autophagy constituting a new frontier in estrogen-related human diseases. Here, we discuss the dual role of ERα in classical and non-classical autophagy through B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). Next, we review the role of ERβ in pro-survival pathways through the promotion of autophagy under stress conditions. We further discuss activation of GPER via estrogen often mediates autophagy or mitophagy suppression, respectively. In summary, we believe that understanding the relationship between estrogen and its receptors mediated-autophagy on cell fate and human diseases will provide insightful knowledge for future therapeutic implications.
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Affiliation(s)
- Yong Wei
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, PR China
| | - Jian Huang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, Hubei, PR China.
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Bhardwaj P, Au CC, Benito-Martin A, Ladumor H, Oshchepkova S, Moges R, Brown KA. Estrogens and breast cancer: Mechanisms involved in obesity-related development, growth and progression. J Steroid Biochem Mol Biol 2019; 189:161-170. [PMID: 30851382 PMCID: PMC6502693 DOI: 10.1016/j.jsbmb.2019.03.002] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/27/2019] [Accepted: 03/01/2019] [Indexed: 12/21/2022]
Abstract
Obesity is a risk factor for estrogen receptor-positive (ER+) breast cancer after menopause. The pro-proliferative effects of estrogens are well characterized and there is a growing body of evidence to also suggest an important role in tumorigenesis. Importantly, obesity not only increases the risk of breast cancer, but it also increases the risk of recurrence and cancer-associated death. Aromatase is the rate-limiting enzyme in estrogen biosynthesis and its expression in breast adipose stromal cells is hypothesized to drive the growth of breast tumors and confer resistance to endocrine therapy in obese postmenopausal women. The molecular regulation of aromatase has been characterized in response to many obesity-related molecules, including inflammatory mediators and adipokines. This review is aimed at providing an overview of our current knowledge in relation to the regulation of estrogens in adipose tissue and their role in driving breast tumor development, growth and progression.
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Affiliation(s)
- Priya Bhardwaj
- Department of Medicine, Weill Cornell Medicine, New York, USA; Graduate School of Medical Sciences, Weill Cornell Medicine, New York, USA
| | - CheukMan C Au
- Department of Medicine, Weill Cornell Medicine, New York, USA
| | | | - Heta Ladumor
- Department of Medicine, Weill Cornell Medicine, New York, USA; Weill Cornell Medicine - Qatar, Doha, Qatar
| | | | - Ruth Moges
- Department of Medicine, Weill Cornell Medicine, New York, USA
| | - Kristy A Brown
- Department of Medicine, Weill Cornell Medicine, New York, USA; Graduate School of Medical Sciences, Weill Cornell Medicine, New York, USA; Department of Physiology, Monash University, Clayton, Victoria, Australia.
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Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 116:135-170. [PMID: 31036290 DOI: 10.1016/bs.apcsb.2019.01.001] [Citation(s) in RCA: 556] [Impact Index Per Article: 92.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The primary female sex hormones, estrogens, are responsible for the control of functions of the female reproductive system, as well as the development of secondary sexual characteristics that appear during puberty and sexual maturity. Estrogens exert their actions by binding to specific receptors, the estrogen receptors (ERs), which in turn activate transcriptional processes and/or signaling events that result in the control of gene expression. These actions can be mediated by direct binding of estrogen receptor complexes to specific sequences in gene promoters (genomic effects), or by mechanisms that do not involve direct binding to DNA (non-genomic effects). Whether acting via direct nuclear effects, indirect non-nuclear actions, or a combination of both, the effects of estrogens on gene expression are controlled by highly regulated complex mechanisms. In this chapter, we summarize the knowledge gained in the past 60years since the discovery of the estrogen receptors on the mechanisms governing estrogen-mediated gene expression. We provide an overview of estrogen biosynthesis, and we describe the main mechanisms by which the female sex hormone controls gene transcription in different tissues and cell types. Specifically, we address the molecular events governing regulation of gene expression via the nuclear estrogen receptors (ERα, and ERβ) and the membrane estrogen receptor (GPER1). We also describe mechanisms of cross-talk between signaling cascades activated by both nuclear and membrane estrogen receptors. Finally, we discuss natural compounds that are able to target specific estrogen receptors and their implications for human health and medical therapeutics.
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Affiliation(s)
- Nathalie Fuentes
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA, United States
| | - Patricia Silveyra
- Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA, United States; The University of North Carolina at Chapel Hill, School of Nursing, Chapel Hill, NC, United States.
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Cabaton NJ, Poupin N, Canlet C, Tremblay-Franco M, Audebert M, Cravedi JP, Riu A, Jourdan F, Zalko D. An Untargeted Metabolomics Approach to Investigate the Metabolic Modulations of HepG2 Cells Exposed to Low Doses of Bisphenol A and 17β-Estradiol. Front Endocrinol (Lausanne) 2018; 9:571. [PMID: 30319551 PMCID: PMC6167423 DOI: 10.3389/fendo.2018.00571] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 09/06/2018] [Indexed: 12/11/2022] Open
Abstract
The model xeno-estrogen bisphenol A (BPA) has been extensively studied over the past two decades, contributing to major advances in the field of endocrine disrupting chemicals research. Besides its well documented adverse effects on reproduction and development observed in rodents, latest studies strongly suggest that BPA disrupts several endogenous metabolic pathways, with suspected steatogenic and obesogenic effects. BPA's adverse effects on reproduction are attributed to its ability to activate estrogen receptors (ERs), but its effects on metabolism and its mechanism(s) of action at low doses are so far only marginally understood. Metabolomics based approaches are increasingly used in toxicology to investigate the biological changes induced by model toxicants and chemical mixtures, to identify markers of toxicity and biological effects. In this study, we used proton nuclear magnetic resonance (1H-NMR) based untargeted metabolite profiling, followed by multivariate statistics and computational analysis of metabolic networks to examine the metabolic modulation induced in human hepatic cells (HepG2) by an exposure to low and very low doses of BPA (10-6M, 10-9M, and 10-12M), vs. the female reference hormone 17β-estradiol (E2, 10-9M, 10-12M, and 10-15M). Metabolomic analysis combined to metabolic network reconstruction highlighted different mechanisms at lower doses of exposure. At the highest dose, our results evidence that BPA shares with E2 the capability to modulate several major metabolic routes that ensure cellular functions and detoxification processes, although the effects of the model xeno-estrogen and of the natural hormone can still be distinguished.
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Affiliation(s)
- Nicolas J. Cabaton
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Nathalie Poupin
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Cécile Canlet
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
- Axiom Platform, MetaToul-MetaboHub, National Infrastructure for Metabolomics and Fluxomics, Toulouse, France
| | - Marie Tremblay-Franco
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
- Axiom Platform, MetaToul-MetaboHub, National Infrastructure for Metabolomics and Fluxomics, Toulouse, France
| | - Marc Audebert
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Jean-Pierre Cravedi
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Anne Riu
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Fabien Jourdan
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Daniel Zalko
- Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France
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Cipolletti M, Solar Fernandez V, Montalesi E, Marino M, Fiocchetti M. Beyond the Antioxidant Activity of Dietary Polyphenols in Cancer: the Modulation of Estrogen Receptors (ERs) Signaling. Int J Mol Sci 2018; 19:E2624. [PMID: 30189583 PMCID: PMC6165334 DOI: 10.3390/ijms19092624] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 08/31/2018] [Accepted: 09/03/2018] [Indexed: 02/07/2023] Open
Abstract
The potential "health benefits" of dietary polyphenols have been ascribed to their direct antioxidant activity and their impact on the regulation of cell and tissue redox balance. However, because of the relative poor bioavailability of many of these compounds, their effects could not be easily explained by the antioxidant action, which may occur only at high circulating and tissue concentrations. Therefore, many efforts have been put forward to clarify the molecular mechanisms underlining the biological effect of polyphenols in physiological and pathological conditions. Polyphenols' bioavailability, metabolism, and their effects on enzyme, membrane, and/or nuclear receptors and intracellular transduction mechanisms may define the overall impact of these compounds on cancer risk and progression, which is still debated and not yet clarified. Polyphenols are able to bind to estrogen receptor α (ERα) and β (ERβ), and therefore induce biological effects in human cells through mimicking or inhibiting the action of endogenous estrogens, even at low concentrations. In this work, the role and effects of food-contained polyphenols in hormone-related cancers will be reviewed, mainly focusing on the different polyphenols' mechanisms of action with particular attention on their estrogen receptor-based effects, and on the consequences of such processes on tumor progression and development.
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Affiliation(s)
- Manuela Cipolletti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
| | | | - Emiliano Montalesi
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
| | - Maria Marino
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
| | - Marco Fiocchetti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
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47
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Fiocchetti M, Cipolletti M, Ascenzi P, Marino M. Dissecting the 17β-estradiol pathways necessary for neuroglobin anti-apoptotic activity in breast cancer. J Cell Physiol 2018; 233:5087-5103. [PMID: 29219195 DOI: 10.1002/jcp.26378] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/27/2017] [Indexed: 12/26/2022]
Abstract
Neuroglobin (NGB) is a relatively recent discovered monomeric heme-protein, which behave in neurons as a sensor of injuring stimuli including oxidative stress, hypoxia, and neurotoxicity. In addition, the anti-apoptotic activity of overexpressed NGB has been reported both in neurons and in cancer cell lines. We recently demonstrated that, NGB functions as a compensatory protein of the steroid hormone 17β-estradiol (E2) protecting cancer cells against the apoptotic death induced by oxidative stress. However, the E2-induced signaling pathways at the root of NGB over-expression and mitochondrial re-localization in breast cancer cells is still elusive. By using a kinase screening library, here, we report that: i) There is a strong positive correlation between NGB and ERα expression and activity in breast cancer cells; ii) The E2-activated phosphatidyl-inositol 3 kinase (PI3K)/protein kinase B (AKT) and protein kinase C (PKC) pathways are necessary to modulate the NGB protein levels; iii) The E2-induced persistent activation of AKT drive NGB to mitochondria; iv) Reactive oxygen species (ROS)-inducing compounds activating rapidly and transiently AKT does not affect the NGB mitochondrial level; and v) High level of NGB into mitochondria are necessary for the pro-survival and anti-apoptotic effect of this globin in cancer cells. As a whole, these results underline the E2 triggered pathways in E2-responsive breast cancer cells that involve NGB as a compensatory protein devoted to cancer cell survival.
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Affiliation(s)
| | | | - Paolo Ascenzi
- Department of Science, University of Roma Tre, Roma, Italy.,Interdepartmental Laboratory for Electron Microscopy, University of Roma Tre, Roma, Italy
| | - Maria Marino
- Department of Science, University of Roma Tre, Roma, Italy
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48
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Orozco-Hernández L, Gutiérrez-Gómez AA, SanJuan-Reyes N, Islas-Flores H, García-Medina S, Galar-Martínez M, Dublán-García O, Natividad R, Gómez-Oliván LM. 17β-Estradiol induces cyto-genotoxicity on blood cells of common carp (Cyprinus carpio). CHEMOSPHERE 2018; 191:118-127. [PMID: 29031051 DOI: 10.1016/j.chemosphere.2017.10.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 09/18/2017] [Accepted: 10/05/2017] [Indexed: 06/07/2023]
Abstract
17β-Estradiol, a natural hormone present at high concentrations in aquatic ecosystems, affects and modifies endocrine function in animals. In recent years research workers have expressed concern over its potential effects on aquatic organisms; however, little is known about its capacity to induce genetic damage or the pro-apoptotic effects of such damage on fish. Therefore, this study aimed to evaluate 17β-estradiol-induced cyto-genotoxicity in blood cells of the common carp Cyprinus carpio exposed to different concentrations (1 ng, 1 μg and 1 mg L-1). Peripheral blood samples were collected and evaluated by comet assay, micronucleus test, determination of caspase-3 activity and TUNEL assay at 12, 24, 48, 72 and 96 h of exposure. Increases in frequency of micronuclei, TUNEL-positive cells and caspase-3 activity were observed, particularly at the highest concentration. In contrast, the comet assay detected significant increases at 24 and 96 h with the 1 μg and 1 ng L-1 concentrations respectively. The set of assays used in the present study constitutes a reliable early warning biomarker for evaluating the toxicity induced by this type of emerging contaminants on aquatic species.
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Affiliation(s)
- Luis Orozco-Hernández
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan s/n. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
| | - Adriana Andrea Gutiérrez-Gómez
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan s/n. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
| | - Nely SanJuan-Reyes
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan s/n. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
| | - Hariz Islas-Flores
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan s/n. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
| | - Sandra García-Medina
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu S/n y Cerrada de Manuel Stampa, Col. Industrial Vallejo, C.P. 007700, Ciudad de México, Mexico
| | - Marcela Galar-Martínez
- Laboratorio de Toxicología Acuática, Departamento de Farmacia, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Unidad Profesional Adolfo López Mateos, Av. Wilfrido Massieu S/n y Cerrada de Manuel Stampa, Col. Industrial Vallejo, C.P. 007700, Ciudad de México, Mexico
| | - Octavio Dublán-García
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan s/n. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico
| | - Reyna Natividad
- Chemical Engineering Lab., Centro Conjunto de Investigación en Química Sustentable UAEM-UNAM, Carretera Toluca-Atlacomulco Km 14.5, Unidad San Cayetano, Toluca, Estado de México, 50200, Mexico
| | - Leobardo Manuel Gómez-Oliván
- Laboratorio de Toxicología Ambiental, Facultad de Química, Universidad Autónoma del Estado de México, Paseo Colón Intersección Paseo Tollocan s/n. Col. Residencial Colón, 50120, Toluca, Estado de México, Mexico.
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Acconcia F, Fiocchetti M, Marino M. Xenoestrogen regulation of ERα/ERβ balance in hormone-associated cancers. Mol Cell Endocrinol 2017; 457:3-12. [PMID: 27816767 DOI: 10.1016/j.mce.2016.10.033] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Revised: 10/31/2016] [Accepted: 10/31/2016] [Indexed: 02/07/2023]
Abstract
The hormone 17β-estradiol (E2) contributes to body homeostasis maintenance by regulating many different physiological functions in both male and female organs. E2 actions in reproductive and non-reproductive tissues rely on a complex net of nuclear and extra-nuclear signal transduction pathways triggered by at least two estrogen receptor subtypes (ERα and ERβ). Consequently, the de-regulation of E2:ER signaling contributes to the pathogenesis of many diseases including cancer. Among other factors, the ERα/ERβ ratio is considered one of the pivotal mechanisms at the root of E2 action in cancer progression. Remarkably, several natural or synthetic exogenous chemicals, collectively called xenoestrogens, bind to ERs and interfere with their signals and intracellular functions. In this review, the molecular mechanism(s) through which xenoestrogens influence ERα and ERβ intracellular concentrations and the consequences of this influence on E2-related cancer will be discussed.
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Affiliation(s)
- Filippo Acconcia
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Marco Fiocchetti
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy
| | - Maria Marino
- Department of Sciences, Section Biomedical Sciences and Technology, University Roma Tre, Viale Guglielmo Marconi, 446, I-00146, Rome, Italy.
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50
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Comitato R, Ambra R, Virgili F. Tocotrienols: A Family of Molecules with Specific Biological Activities. Antioxidants (Basel) 2017; 6:antiox6040093. [PMID: 29156559 PMCID: PMC5745503 DOI: 10.3390/antiox6040093] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 11/08/2017] [Accepted: 11/16/2017] [Indexed: 01/15/2023] Open
Abstract
Vitamin E is a generic term frequently used to group together eight different molecules, namely: α-, β-, γ- and δ-tocopherol and the corresponding tocotrienols. The term tocopherol and eventually Vitamin E and its related activity was originally based on the capacity of countering foetal re-absorption in deficient rodents or the development of encephalomalacia in chickens. In humans, Vitamin E activity is generally considered to be solely related to the antioxidant properties of the tocolic chemical structure. In recent years, several reports have shown that specific activities exist for each different tocotrienol form. In this short review, tocotrienol ability to inhibit cancer cell growth and induce apoptosis thanks to specific mechanisms, not shared by tocopherols, such as the binding to Estrogen Receptor-β (ERβ) and the triggering of endoplasmic reticulum (EndoR) stress will be described. The neuroprotective activity will also be presented and discussed. We propose that available studies strongly indicate that specific forms of tocotrienols have a distinct mechanism and biological activity, significantly different from tocopherol and more specifically from α-tocopherol. We therefore suggest not pooling them together within the broad term “Vitamin E” on solely the basis of their putative antioxidant properties. This option implies obvious consequences in the assessment of dietary Vitamin E adequacy and, probably more importantly, on the possibility of evaluating a separate biological variable, determinant in the relationship between diet and health.
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Affiliation(s)
- Raffaella Comitato
- Council for Agricultural Research and Economics, Research Centre for Food and Nutrition (CREA-AN) via Ardeatina 546, 00178 Rome, Italy.
| | - Roberto Ambra
- Council for Agricultural Research and Economics, Research Centre for Food and Nutrition (CREA-AN) via Ardeatina 546, 00178 Rome, Italy.
| | - Fabio Virgili
- Council for Agricultural Research and Economics, Research Centre for Food and Nutrition (CREA-AN) via Ardeatina 546, 00178 Rome, Italy.
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