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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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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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Saúco C, Rus MJ, Nieto MR, Barros C, Cantiga-Silva C, Lendines-Cordero D, Calderer-Ortiz M, Zurita-García M, Arias-Herrera S, Monsalve-Guil L, Segura-Egea JJ, Simon-Soro A. Hyposalivation but not Sjögren's syndrome associated with microbial dysbiosis in women. Front Microbiol 2023; 14:1240891. [PMID: 37869670 PMCID: PMC10588445 DOI: 10.3389/fmicb.2023.1240891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 09/18/2023] [Indexed: 10/24/2023] Open
Abstract
Background Saliva modulates the environment of the oral biofilm through pH buffer, microbial attachment to host surfaces, and nutritional source. The ecology of stress occurs when a physical factor adversely impacts an ecosystem or its biotic components. Therefore, reduced salivary flow can affect oral-host balance. The leading causes of hyposalivation include disease-associated Sjögren's syndrome (SS) and menopausal women as aging-associated. However, little is known about the oral microbiome integrated with sex hormones in hyposalivation. This study aimed to characterize the hyposalivation microbiome caused by aging or disease affecting the salivary glands in women. Methods We included 50 women older than 40 years of age in any menopausal phase. We collected stimulated saliva from 25 women diagnosed with SS (SS) and 25 without SS (non-SS). The bacterial profile of the patients was obtained by 16S rRNA sequencing. Bioinformatics analysis used machine learning to analyze the cohort's signs, symptoms, and bacterial profile. Salivary estradiol as a sex hormone variation level was determined. Results We obtained that 79% of the SS group, and 52% of the non-SS group had hyposalivation. We found a negatively correlated Prevotella-age and Rothia-estradiol in the SS group. Highlight, we found that the cause of the hyposalivation in the study did not explain differences in microbial diversity comparing non-SS and SS groups. Therefore, microbial communities found in hyposalivation but not related to systemic conditions suggest that changes in the oral environment might underpin host-microbial balance. Conclusion The salivary microbiome was similar in women with and without SS. However, hyposalivation showed two distinctive clusters associated with the bacterial population profiles. Our study suggests that local ecological disturbances could drive the change in the microbiome.
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Affiliation(s)
- Carlos Saúco
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - Maria J. Rus
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - María R. Nieto
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - Carolina Barros
- Department of Preventive and Restorative Dentistry, Dental School, São Paulo State University (UNESP), Araçatuba, Brazil
| | - Cristiane Cantiga-Silva
- Department of Preventive and Restorative Dentistry, Dental School, São Paulo State University (UNESP), Araçatuba, Brazil
| | | | - Marta Calderer-Ortiz
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - Miriam Zurita-García
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - Santiago Arias-Herrera
- Department of Dentistry, Faculty of Health Sciences, Universidad Europea de Valencia, Valencia, Spain
| | - Loreto Monsalve-Guil
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - Juan José Segura-Egea
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
| | - Aurea Simon-Soro
- Department of Stomatology, Faculty of Dentistry, University of Seville, Seville, Spain
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Liu Y, Liu J, Peng N, Hai S, Zhang S, Zhao H, Liu W. Role of non-canonical post-translational modifications in gastrointestinal tumors. Cancer Cell Int 2023; 23:225. [PMID: 37777749 PMCID: PMC10544213 DOI: 10.1186/s12935-023-03062-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/08/2023] [Indexed: 10/02/2023] Open
Abstract
Post-translational modifications (PTMs) of proteins contribute to the occurrence and development of tumors. Previous studies have suggested that canonical PTMs such as ubiquitination, glycosylation, and phosphorylation are closely implicated in different aspects of gastrointestinal tumors. Recently, emerging evidence showed that non-canonical PTMs play an essential role in the carcinogenesis, metastasis and treatment of gastrointestinal tumors. Therefore, we summarized recent advances in sumoylation, neddylation, isoprenylation, succinylation and other non-canonical PTMs in gastrointestinal tumors, which comprehensively describe the mechanisms and functions of non-classical PTMs in gastrointestinal tumors. It is anticipated that targeting specific PTMs could benefit the treatment as well as improve the prognosis of gastrointestinal tumors.
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Affiliation(s)
- Yihong Liu
- Department of Gastroenterology, the First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China
| | - Jingwei Liu
- Department of Anus and Intestine Surgery, the First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Na Peng
- Department of Gastroenterology, the First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China
| | - Shuangshuang Hai
- Department of Gastroenterology, the First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China
| | - Shen Zhang
- Department of Gastroenterology, the Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Haibo Zhao
- Department of Gastroenterology, the First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China
| | - Weixin Liu
- Department of Gastroenterology, the First Affiliated Hospital of China Medical University, 155# North Nanjing Street, Heping District, Shenyang City, 110001, Liaoning Province, China.
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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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Li P, Gong X, Yuan L, Mu L, Zheng Q, Xiao H, Wang H. Palmitoylation in apoptosis. J Cell Physiol 2023; 238:1641-1650. [PMID: 37260091 DOI: 10.1002/jcp.31047] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 04/26/2023] [Accepted: 05/08/2023] [Indexed: 06/02/2023]
Abstract
Palmitoylation, a critical lipid modification of proteins, is involved in various physiological processes such as altering protein localization, transport, and stability, which perform essential roles in protein function. Palmitoyltransferases are specific enzymes involved in the palmitoylation modification of substrates. S-palmitoylation, as the only reversible palmitoylation modification, is able to be deacylated by deacyltransferases. As an important mode of programmed cell death, apoptosis functions in the maintenance of organismal homeostasis as well as being associated with inflammatory and immune diseases. Recently, studies have found that palmitoylation and apoptosis have been demonstrated to be related in many human diseases. In this review, we will focus on the role of palmitoylation modifications in apoptosis.
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Affiliation(s)
- Peiyao Li
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Xiaoyi Gong
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Lei Yuan
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Lina Mu
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Qian Zheng
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Hui Xiao
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
| | - Hui Wang
- Department of Cell and Development Biology, College of Life Sciences, Shaanxi Normal University, Xi'an, China
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7
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Tokiwa H, Ueda K, Takimoto E. The emerging role of estrogen's non-nuclear signaling in the cardiovascular disease. Front Cardiovasc Med 2023; 10:1127340. [PMID: 37123472 PMCID: PMC10130590 DOI: 10.3389/fcvm.2023.1127340] [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: 12/19/2022] [Accepted: 03/24/2023] [Indexed: 05/02/2023] Open
Abstract
Sexual dimorphism exists in the epidemiology of cardiovascular disease (CVD), which indicates the involvement of sexual hormones in the pathophysiology of CVD. In particular, ample evidence has demonstrated estrogen's protective effect on the cardiovascular system. While estrogen receptors, bound to estrogen, act as a transcription factor which regulates gene expressions by binding to the specific DNA sequence, a subpopulation of estrogen receptors localized at the plasma membrane induces activation of intracellular signaling, called "non-nuclear signaling" or "membrane-initiated steroid signaling of estrogen". Although the precise molecular mechanism of non-nuclear signaling as well as its physiological impact was unclear for a long time, recent development of genetically modified animal models and pathway-selective estrogen receptor stimulant bring new insights into this pathway. We review the published experimental studies on non-nuclear signaling of estrogen, and summarize its role in cardiovascular system, especially focusing on: (1) the molecular mechanism of non-nuclear signaling; (2) the design of genetically modified animals and pathway-selective stimulant of estrogen receptor.
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Affiliation(s)
- Hiroyuki Tokiwa
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazutaka Ueda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Eiki Takimoto
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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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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Mahbub AA. 17β-estradiol Enhances 5-Fluorouracil Anti-Cancer Activities in Colon Cancer Cell Lines. MEDICAL SCIENCES (BASEL, SWITZERLAND) 2022; 10:medsci10040062. [PMID: 36412903 PMCID: PMC9680382 DOI: 10.3390/medsci10040062] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/24/2022] [Accepted: 10/27/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND 5-Fluorouracil (5-FU) represents one of the major constituents of chemotherapy combination regimens in colon cancer (CRC) treatments; however, this regimen is linked with severe adverse effects and chemoresistance. Thus, developing more efficient approaches for CRC is urgently needed to overcome these problems and improve the patient survival rate. Currently, 17β-estradiol (E2) has gained greater attention in colon carcinogenesis, significantly lowering the incidence of CRC in females at reproductive age compared with age-matched males. AIMS This study measured the effects of E2 and/or 5-FU single/dual therapies on cell cycle progression and apoptosis against human HT-29 female and SW480 male primary CRC cells versus their impact on SW620 male metastatic CRC cells. METHODS The HT-29, SW480, and SW620 cells were treated with IC50 of E2 (10 nM) and 5-FU (50 μM), alone or combined (E+F), for 48 h before cell cycle and apoptosis analyses using flow cytometry. RESULTS The data here showed that E2 monotherapy has great potential to arrest the cell cycle and induce apoptosis in all the investigated colon cancer cells, with the most remarkable effects on metastatic cells (SW620). Most importantly, the dual therapy (E+F) has exerted anti-cancer activities in female (HT-29) and male (SW480) primary CRC cells by inducing apoptosis, which was preferentially provoked in the sub-G1 phase. However, the dual treatment showed the smallest effect in SW620 metastatic cells. CONCLUSION this is the first study that demonstrated that the anti-cancer actions of 17β-estradiol and 5-Fluorouracil dual therapy were superior to the monotherapies in female and male primary CRC cells; it is proposed that this treatment strategy could be promising for the early stages of CRC. At the same time, 17β-estradiol monotherapy could be a better approach for treating the metastatic forms of the disease. Nevertheless, additional investigations are still required to determine their precise therapeutic values in CRC.
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Affiliation(s)
- Amani A Mahbub
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, P.O. Box 715, Makkah 21955, Saudi Arabia
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10
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Zhou B, Hao Q, Liang Y, Kong E. Protein palmitoylation in cancer: molecular functions and therapeutic potential. Mol Oncol 2022; 17:3-26. [PMID: 36018061 PMCID: PMC9812842 DOI: 10.1002/1878-0261.13308] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/30/2022] [Accepted: 08/16/2022] [Indexed: 02/03/2023] Open
Abstract
Protein S-palmitoylation (hereinafter referred to as protein palmitoylation) is a reversible lipid posttranslational modification catalyzed by the zinc finger DHHC-type containing (ZDHHC) protein family. The reverse reaction, depalmitoylation, is catalyzed by palmitoyl-protein thioesterases (PPTs), including acyl-protein thioesterases (APT1/2), palmitoyl protein thioesterases (PPT1/2), or alpha/beta hydrolase domain-containing protein 17A/B/C (ABHD17A/B/C). Proteins encoded by several oncogenes and tumor suppressors are modified by palmitoylation, which enhances the hydrophobicity of specific protein subdomains, and can confer changes in protein stability, membrane localization, protein-protein interaction, and signal transduction. The importance for protein palmitoylation in tumorigenesis has just started to be elucidated in the past decade; palmitoylation appears to affect key aspects of cancer, including cancer cell proliferation and survival, cell invasion and metastasis, and antitumor immunity. Here we review the current literature on protein palmitoylation in the various cancer types, and discuss the potential of targeting of palmitoylation enzymes or palmitoylated proteins for tumor treatment.
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Affiliation(s)
- Binhui Zhou
- Institute of Psychiatry and NeuroscienceXinxiang Medical UniversityChina,Laboratory of Genetic Regulators in the Immune System, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory MedicineXinxiang Medical UniversityChina
| | - Qianyun Hao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Oncology IIPeking University Cancer Hospital & InstituteBeijingChina
| | - Yinming Liang
- Institute of Psychiatry and NeuroscienceXinxiang Medical UniversityChina,Laboratory of Genetic Regulators in the Immune System, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory MedicineXinxiang Medical UniversityChina,Henan Key Laboratory of Immunology and Targeted Therapy, School of Laboratory MedicineXinxiang Medical UniversityChina
| | - Eryan Kong
- Institute of Psychiatry and NeuroscienceXinxiang Medical UniversityChina
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Xia X, Lin Q, Zhao N, Zeng J, Yang J, Liu Z, Huang R. Anti-Colon Cancer Activity of Dietary Phytochemical Soyasaponin I and the Induction of Metabolic Shifts in HCT116. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27144382. [PMID: 35889255 PMCID: PMC9316303 DOI: 10.3390/molecules27144382] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 06/26/2022] [Accepted: 07/06/2022] [Indexed: 12/24/2022]
Abstract
Dietary phytochemicals play an important role in the prevention and treatment of colon cancer. It is reported that group B of soyasaponin, derived from dietary pulses, has anti-colonic effects on some colon cancer cell lines. However, it is uncertain which specific soybean saponins play a role. In our study, as one of the group B soyasaponin, the anti-colon cancer activity of soyasaponins I (SsI) was screened, and we found that it had the inhibitory effect of proliferation on colon cancer cell lines HCT116 (IC50 = 161.4 μM) and LoVo (IC50 = 180.5 μM), but no effect on HT29 between 0–200 μM. Then, nine potential targets of SsI on colon cancer were obtained by network pharmacology analysis. A total of 45 differential metabolites were identified by metabolomics analysis, and the KEGG pathway was mainly enriched in the pathways related to the absorption and metabolism of amino acids. Finally, molecular docking analysis predicted that SsI might dock with the protein of DNMT1, ERK1. The results indicated that the effect of SsI on HCT116 might be exerted by influencing amino acid metabolism and the estrogen signaling pathway. This study may provide the possibility for the application of SsI against colon cancer.
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Affiliation(s)
- Xuewei Xia
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China; (X.X.); (Q.L.); (J.Z.); (J.Y.); (Z.L.)
| | - Qianmin Lin
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China; (X.X.); (Q.L.); (J.Z.); (J.Y.); (Z.L.)
| | - Ning Zhao
- Graduate School, Guangzhou University of Chinese Medicine, Guangzhou 510006, China;
| | - Jinzi Zeng
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China; (X.X.); (Q.L.); (J.Z.); (J.Y.); (Z.L.)
| | - Jiajia Yang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China; (X.X.); (Q.L.); (J.Z.); (J.Y.); (Z.L.)
| | - Zhiyuan Liu
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China; (X.X.); (Q.L.); (J.Z.); (J.Y.); (Z.L.)
| | - Riming Huang
- Guangdong Provincial Key Laboratory of Food Quality and Safety, College of Food Science, South China Agricultural University, Guangzhou 510642, China; (X.X.); (Q.L.); (J.Z.); (J.Y.); (Z.L.)
- Correspondence:
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12
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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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13
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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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14
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TSH Combined with TSHR Aggravates Diabetic Peripheral Neuropathy by Promoting Oxidative Stress and Apoptosis in Schwann Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2482453. [PMID: 34804362 PMCID: PMC8601831 DOI: 10.1155/2021/2482453] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/29/2021] [Accepted: 10/19/2021] [Indexed: 11/17/2022]
Abstract
Subclinical hypothyroidism (SCH) is associated with diabetic peripheral neuropathy (DPN); however, the mechanism underlying this association remains unknown. This study is aimed at examining neurofunctional and histopathological alterations in a type 2 diabetes (T2DM) mouse model of SCH and investigating the impact of thyroid-stimulating hormone (TSH) in an in vitro DPN cell model established using RSC96 cells under high glucose (HG) and palmitic acid (PA) stimulation. Our results indicated that T2DM, in combination with SCH, aggravated abnormal glucose and lipid metabolism in T2DM and dramatically destroyed the peripheral nervous system by increasing paw withdrawal latency, decreasing motor nerve conduction velocity, and exacerbating ultrastructural deterioration of the damaged sciatic nerve caused by diabetes. Furthermore, the results of our in vitro experiments showed that TSH intensified HG/PA-induced RSC96 cell damage by inducing oxidative stress, mitochondrial dysfunction, and apoptosis. More importantly, TSHR knockout or inhibition of PA-induced TSHR palmitoylation could alleviate the apoptosis induced by TSH. Overall, in this study, the novel mechanisms by which TSH, as an independent risk factor for DPN progression, aggravating Schwann cell apoptosis and demyelination, are elucidated. These findings indicate that TSHR could be a potential target for both the prevention and treatment of DPN and, possibly, other microvascular diseases, and have implication in the clinical management of patients with DPN.
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15
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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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16
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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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17
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Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy. Int J Mol Sci 2020; 21:ijms21124349. [PMID: 32570961 PMCID: PMC7352873 DOI: 10.3390/ijms21124349] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 06/10/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022] Open
Abstract
Normal pregnancy is associated with dramatic increases in uterine blood flow to facilitate the bidirectional maternal–fetal exchanges of respiratory gases and to provide sole nutrient support for fetal growth and survival. The mechanism(s) underlying pregnancy-associated uterine vasodilation remain incompletely understood, but this is associated with elevated estrogens, which stimulate specific estrogen receptor (ER)-dependent vasodilator production in the uterine artery (UA). The classical ERs (ERα and ERβ) and the plasma-bound G protein-coupled ER (GPR30/GPER) are expressed in UA endothelial cells and smooth muscle cells, mediating the vasodilatory effects of estrogens through genomic and/or nongenomic pathways that are likely epigenetically modified. The activation of these three ERs by estrogens enhances the endothelial production of nitric oxide (NO), which has been shown to play a key role in uterine vasodilation during pregnancy. However, the local blockade of NO biosynthesis only partially attenuates estrogen-induced and pregnancy-associated uterine vasodilation, suggesting that mechanisms other than NO exist to mediate uterine vasodilation. In this review, we summarize the literature on the role of NO in ER-mediated mechanisms controlling estrogen-induced and pregnancy-associated uterine vasodilation and our recent work on a “new” UA vasodilator hydrogen sulfide (H2S) that has dramatically changed our view of how estrogens regulate uterine vasodilation in pregnancy.
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18
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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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19
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Wang Y, Lu H, Fang C, Xu J. Palmitoylation as a Signal for Delivery. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1248:399-424. [DOI: 10.1007/978-981-15-3266-5_16] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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20
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Estrogen receptor-beta is a potential target for triple negative breast cancer treatment. Oncotarget 2018; 9:33912-33930. [PMID: 30338035 PMCID: PMC6188058 DOI: 10.18632/oncotarget.26089] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 07/12/2018] [Indexed: 12/31/2022] Open
Abstract
Triple Negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2. TNBC accounts for 15-20% of all breast cancer cases but accounts for over 50% of mortality. We propose that Estrogen receptor-beta (ERβ) and IGF2 play a significant role in the pathogenesis of TNBCs, and could be important targets for future therapy. Tissue microarrays (TMAs) from over 250 TNBC patients' were analyzed for ERβ and IGF2 expression by immunohistochemistry. Expression was correlated with clinical outcomes. In addition, TNBC cell lines Caucasians (CA): MB-231/BT549 and African Americans (AAs): MB-468/HCC70/HCC1806 were used to investigate the effect of hormonal and growth factor regulation on cell proliferation. TMAs from AAs had higher expression of ERβ and IGF2 expression when compared to CA. ERβ and IGF2 were found to be upregulated in our TNBC cell lines when compared to other cell types. TNBC cells treated with ERβ agonist displayed significant increase in cell proliferation and migration when compared to controls. AA tissue samples from TNBC patients had higher expression of ERβ. African-American breast cancer TNBC tissue samples from TNBC patients have higher expression of ERβ. In addition, TNBC cell lines were also found to express high levels of ERβ. IGF2 increased transcription of ERβ in TNBC cells. Understanding the mechanisms of IGF2/ERβ axis in TNBC tumors could provide an opportunity to target this aggressive subtype of breast cancer.
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21
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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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22
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Kow LM, Pfaff DW. Can distinctly different rapid estrogen actions share a common mechanistic step? Horm Behav 2018; 104:156-164. [PMID: 29476777 DOI: 10.1016/j.yhbeh.2018.02.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/15/2018] [Accepted: 02/19/2018] [Indexed: 12/23/2022]
Abstract
Contribution to Special Issue on Fast effects of steroids. This paper reviews early evidence for the existence of rapid, non-genomic effects of estrogens on neurons, and, further, proposes that these rapid effects are often synergistic with later, genomic effects. Finally, suggestions about potential molecular mechanisms underlying the rapid effects of estrogens are offered. A mechanistic step we propose to be common among rapid estrogenic actions includes membrane ER's binding to histamine, and NMDA receptors and subsequent dimerization, and clustering (respectively) in a manner that enhances histamine and NMDA actions.
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Affiliation(s)
- Lee-Ming Kow
- Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, United States.
| | - Donald W Pfaff
- Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, United States
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23
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Nie X, Xie R, Tuo B. Effects of Estrogen on the Gastrointestinal Tract. Dig Dis Sci 2018; 63:583-596. [PMID: 29387989 DOI: 10.1007/s10620-018-4939-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 01/19/2018] [Indexed: 02/06/2023]
Abstract
Estrogen is a kind of steroid compound that has extensive biologic activities. The effect of estrogen is pleiotropic, affecting multiple systems in the body. There is accumulating evidence that estrogen has important effects on the gastrointestinal tract. Longer exposure to estrogen may decrease the risk of gastric cancer. Use of the anti-estrogen drug tamoxifen might increase the risk of gastric adenocarcinoma. Estrogen receptor β may serve as a target for colorectal cancer prevention. In addition, estrogen has been reported to be closely related to the mucosal barrier, gastrointestinal function and intestinal inflammation. However, the role of estrogen in the gastrointestinal tract has not been systematically summarized. In this review, we aim to provide an overview of the role of estrogen in the gastrointestinal tract and evaluate it from various aspects, including estrogen receptors, the mucosal barrier, intestinal inflammation and gastrointestinal tract tumors, which may provide the basis for the development of therapeutic strategies to manage gastrointestinal diseases.
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Affiliation(s)
- Xubiao Nie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, 149 Dalian Road, Zunyi, 563003, China.
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24
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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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25
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Dostalova P, Zatecka E, Dvorakova-Hortova K. Of Oestrogens and Sperm: A Review of the Roles of Oestrogens and Oestrogen Receptors in Male Reproduction. Int J Mol Sci 2017; 18:ijms18050904. [PMID: 28441342 PMCID: PMC5454817 DOI: 10.3390/ijms18050904] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/31/2017] [Accepted: 04/20/2017] [Indexed: 01/08/2023] Open
Abstract
The crucial role that oestrogens play in male reproduction has been generally accepted; however, the exact mechanism of their action is not entirely clear and there is still much more to be clarified. The oestrogen response is mediated through oestrogen receptors, as well as classical oestrogen receptors’ variants, and their specific co-expression plays a critical role. The importance of oestrogen signalling in male fertility is indicated by the adverse effects of selected oestrogen-like compounds, and their interaction with oestrogen receptors was proven to cause pathologies. The aims of this review are to summarise the current knowledge on oestrogen signalling during spermatogenesis and sperm maturation and discuss the available information on oestrogen receptors and their splice variants. An overview is given of species-specific differences including in humans, along with a detailed summary of the methodology outcome, including all the genetically manipulated models available to date. This review provides coherent information on the recently discovered mechanisms of oestrogens’ and oestrogen receptors’ effects and action in both testicular somatic and germ cells, as well as in mature sperm, available for mammals, including humans.
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Affiliation(s)
- Pavla Dostalova
- Group of Reproductive Biology, Institute of Biotechnology CAS, v.v.i., BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic.
| | - Eva Zatecka
- Group of Reproductive Biology, Institute of Biotechnology CAS, v.v.i., BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic.
| | - Katerina Dvorakova-Hortova
- Group of Reproductive Biology, Institute of Biotechnology CAS, v.v.i., BIOCEV, Prumyslova 595, 25250 Vestec, Czech Republic.
- Department of Zoology, Faculty of Science, Charles University, Vinicna 7, 12844 Prague 2, Czech Republic.
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26
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Yaşar P, Ayaz G, User SD, Güpür G, Muyan M. Molecular mechanism of estrogen-estrogen receptor signaling. Reprod Med Biol 2016; 16:4-20. [PMID: 29259445 PMCID: PMC5715874 DOI: 10.1002/rmb2.12006] [Citation(s) in RCA: 294] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/16/2016] [Indexed: 02/06/2023] Open
Abstract
17β‐Estradiol (E2), as the main circulating estrogen hormone, regulates many tissue and organ functions in physiology. The effects of E2 on cells are mediated by the transcription factors and estrogen receptor (ER)α and ERβ that are encoded by distinct genes. Localized at the peri‐membrane, mitochondria, and the nucleus of cells that are dependent on estrogen target tissues, the ERs share similar, as well as distinct, regulatory potentials. Different intracellular localizations of the ERs result in dynamically integrated and finely tuned E2 signaling cascades that orchestrate cellular growth, differentiation, and death. The deregulation of E2–ER signaling plays a critical role in the initiation and progression of target tissue malignancies. A better understanding of the complex regulatory mechanisms that underlie ER actions in response to E2 therefore holds a critical trajectory for the development of novel prognostic and therapeutic approaches with substantial impacts on the systemic management of target tissue diseases.
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Affiliation(s)
- Pelin Yaşar
- Department of Biological Sciences Middle East Technical University Ankara Turkey
| | - Gamze Ayaz
- Department of Biological Sciences Middle East Technical University Ankara Turkey
| | - Sırma Damla User
- Department of Biological Sciences Middle East Technical University Ankara Turkey
| | - Gizem Güpür
- Department of Biological Sciences Middle East Technical University Ankara Turkey.,Present address: Cell and Molecular Biology Program Duke University Durham North Carolina USA
| | - Mesut Muyan
- Department of Biological Sciences Middle East Technical University Ankara Turkey
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27
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Levin ER, Hammes SR. Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nat Rev Mol Cell Biol 2016; 17:783-797. [PMID: 27729652 PMCID: PMC5649368 DOI: 10.1038/nrm.2016.122] [Citation(s) in RCA: 200] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Steroid hormone receptors mediate numerous crucial biological processes and are classically thought to function as transcriptional regulators in the nucleus. However, it has been known for more than 50 years that steroids evoke rapid responses in many organs that cannot be explained by gene regulation. Mounting evidence indicates that most steroid receptors in fact exist in extranuclear cellular pools, including at the plasma membrane. This latter pool, when engaged by a steroid ligand, rapidly activates signals that affect various aspects of cellular biology. Research into the mechanisms of signalling instigated by extranuclear steroid receptor pools and how this extranuclear signalling is integrated with responses elicited by nuclear receptor pools provides novel understanding of steroid hormone signalling and its roles in health and disease.
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Affiliation(s)
- Ellis R. Levin
- Department of Medicine and Biochemistry, University of California,
Irvine and the Long Beach VA Medical Center, California 90822, USA
| | - Stephen R. Hammes
- Departments of Medicine and Pharmacology, University of Rochester,
Rochester, New York 14642, USA
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28
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Ascenzi P, di Masi A, Leboffe L, Fiocchetti M, Nuzzo MT, Brunori M, Marino M. Neuroglobin: From structure to function in health and disease. Mol Aspects Med 2016; 52:1-48. [DOI: 10.1016/j.mam.2016.10.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 10/27/2016] [Accepted: 10/27/2016] [Indexed: 01/01/2023]
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29
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Anderson AM, Ragan MA. Palmitoylation: a protein S-acylation with implications for breast cancer. NPJ Breast Cancer 2016; 2:16028. [PMID: 28721385 PMCID: PMC5515344 DOI: 10.1038/npjbcancer.2016.28] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 07/25/2016] [Accepted: 07/27/2016] [Indexed: 12/19/2022] Open
Abstract
Protein S-acylation is a reversible post-translational lipid modification that involves linkage of a fatty acid chain predominantly to a cysteine amino acid via a thioester bond. The fatty acid molecule is primarily palmitate, thus the term 'palmitoylation' is more commonly used. Palmitoylation has been found to modulate all stages of protein function including maturational processing, trafficking, membrane anchoring, signaling range and efficacy, and degradation. In breast cancer, palmitoylation has been shown to control the function of commonly dysregulated genes including estrogen receptors, the epidermal growth factor (EGF) family of receptors, and cancer stem cell markers. Importantly, palmitoylation is a critical factor controlling the formation of complexes at the plasma membrane involving tetraspanins, integrins, and gene products that are key to cell-cell communication. During metastasis, cancer cells enhance their metastatic capacity by interacting with stroma and immune cells. Although aberrant palmitoylation could contribute to tumor initiation and growth, its potential role in these cell-cell interactions is of particular interest, as it may provide mechanistic insight into metastasis, including cancer cell-driven immune modulation. Compelling evidence for a role for aberrant palmitoylation in breast cancer remains to be established. To this end, in this review we summarize emerging evidence and highlight pertinent knowledge gaps, suggesting directions for future research.
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Affiliation(s)
- Alison M Anderson
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
| | - Mark A Ragan
- Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
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30
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Campesi I, Marino M, Montella A, Pais S, Franconi F. Sex Differences in Estrogen Receptor α and β Levels and Activation Status in LPS-Stimulated Human Macrophages. J Cell Physiol 2016; 232:340-345. [PMID: 27171902 DOI: 10.1002/jcp.25425] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 05/09/2016] [Indexed: 12/11/2022]
Abstract
Immune function, inflammation, and atherosclerosis display sex differences and are influenced by 17β-estradiol through estrogen receptors subtypes ERα and ERβ. Male tissues express active ERs, but their possible involvement in inflammation in males has never been assessed. Macrophages express both ERα and ERβ and offer the opportunity to evaluate the role of ER levels and activation in inflammation. We assessed the ability of lipopolysaccharide (LPS) to modulate, in a sex-specific way, the expression and the activation status of ERα and ERβ in blood monocytes-derived macrophages (MDMs) from men and women. MDMs were incubated with 100 ng/ml LPS for 24 h and used to evaluate ERα, ERβ, P-ERα, p38, and P-p38 expression by Western Blotting. In basal conditions, ERα and ERβ were significantly higher in female MDMs than in male MDMs. LPS up-regulated ERα and ERα phosphorylation in both sexes, with a significantly higher effect observed in male MDMs, and down-regulated ERβ level only in female MDMs. p38 and P-p38 proteins, indicative of ERβ activity, did not show sex differences both in basal conditions and after LPS treatment. Finally, ERα/ERβ and P-ERα/ERα ratios were significantly higher in male MDMs than in female ones. Our data indicate, for the first time, that LPS affects ERα but not ERβ activation status. We identify a significant role of ERα in LPS-mediated inflammatory responses in MDMs, which represents an initial step in understanding the influence of sex in the relationship between LPS and ERα. J. Cell. Physiol. 232: 340-345, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ilaria Campesi
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy. .,Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Osilo, Italy.
| | - Maria Marino
- Cell Physiology Lab, Department of Science, University Roma Tre, Rome, Italy.
| | - Andrea Montella
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Sara Pais
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Flavia Franconi
- Department of Biomedical Sciences, University of Sassari, Sassari, Italy.,Assessorato alle Politiche per la Persona of Basilicata Region, Potenza, Italy
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31
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Chavoshinejad R, Marei WFA, Hartshorne GM, Fouladi-Nashta AA. Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells. Reprod Fertil Dev 2016; 28:765-75. [DOI: 10.1071/rd14294] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 09/23/2014] [Indexed: 12/14/2022] Open
Abstract
The aim of the present study was to investigate the hormonal regulation of hyaluronan (HA) components in sheep granulosa cells. HA components are present in the reproductive tract and have a range of physical and signalling properties related to reproductive function in several species. First, abattoir-derived ovaries of sheep were used to determine the localisation of HA synthase (HAS) 1–3 and CD44 proteins in antral follicles. Staining for HAS1–3 and CD44 proteins was most intense in the granulosa layer. Accordingly, the expression of HAS2, HAS3 and CD44 mRNA was measured in cultured granulosa cells exposed to 0–50 ng mL–1 of 17β-oestradiol and different combinations of oestradiol, gonadotropins, insulin-like growth factor (IGF)-1 and insulin for 48–96 h (1 ng mL–1 FSH, 10 ng mL–1 insulin, 10 ng mL–1 IGF-1, 40 ng mL–1 E2 and 25 ng mL–1 LH.). mRNA expression was quantified by real-time polymerase chain reaction using a fold induction method. The results revealed that the hormones tested generally stimulated mRNA expression of the genes of interest in cultured granulosa cells. Specifically, oestradiol, when combined with IGF-1, insulin and FSH, stimulated HAS2 mRNA expression. Oestradiol and LH had synergistic effects in increasing HAS3 mRNA expression. In conclusion, we suggest that the hormones studied differentially regulate HAS2, HAS3 and CD44 in ovine granulosa cells in vitro. Further work is needed to address the signalling pathways involved.
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32
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Wang ZY, Yin L. Estrogen receptor alpha-36 (ER-α36): A new player in human breast cancer. Mol Cell Endocrinol 2015; 418 Pt 3:193-206. [PMID: 25917453 DOI: 10.1016/j.mce.2015.04.017] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Revised: 04/20/2015] [Accepted: 04/20/2015] [Indexed: 01/16/2023]
Abstract
Prevailing wisdom is that estrogen receptor (ER)-α mediated genomic estrogen signaling is responsible for estrogen-stimulated cell proliferation and development of ER-positive breast cancer. However, accumulating evidence indicates that another estrogen signaling pathway, non-genomic or rapid estrogen signaling, also plays an important role in mitogenic estrogen signaling. Previously, our laboratory cloned a 36 kDa variant of ER-α, ER-α36, and found that ER-α36 is mainly expressed in the cytoplasm and at the plasma membrane. ER-α36 mediates rapid estrogen signaling and inhibits genomic estrogen signaling. In this review, we review and update the biological function of ER-α36 in ER-positive and -negative breast cancer, breast cancer stem/progenitor cells and tamoxifen resistance, potential interaction and cross-talk of ER-α36 with other ERs and growth factor receptors, and intracellular pathways of ER-α36-mediated rapid estrogen signaling. The potential function and underlying mechanism of ER-α in development of ER-positive breast cancer will also be discussed.
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Affiliation(s)
- Zhao-Yi Wang
- Department of Medical Microbiology & Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA.
| | - Li Yin
- Department of Medical Microbiology & Immunology, Creighton University Medical School, 2500 California Plaza, Omaha, NE 68178, USA
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33
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Estrogen receptor β expression and colorectal cancer: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2015; 27:1438-42. [PMID: 26367493 DOI: 10.1097/meg.0000000000000471] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Estrogen receptor β (ERβ) is a potential tumor-suppressor gene in colorectal cancer (CRC). This hypothesis is supported by clinical and laboratory observations. AIM In this meta-analysis, we looked at studies that investigated the relationship between ERβ protein expression and CRC, comparing the lesion with normal adjacent mucosa. METHODS English medical literature searches were performed for ERβ expression in patients with CRC, tumor tissue versus normal mucosa. Searches were performed up to 31 May 2015, using MEDLINE, PubMed, EMBASE, Scopus, and CENTRAL. Meta-analysis was carried out using Comprehensive Meta-analysis Software. Pooled odds ratios and 95% confidence intervals were calculated and ERβ expression was compared in individual studies using the fixed-effects model. RESULTS The odds ratio of ERβ expression was 0.216 (95% confidence interval 0.152-0.307, P<0.0001), lower in cancer tissue than normal mucosa. Funnel plot did not indicate a significant publication bias. There was no significant heterogeneity in the studies included: Q=5.897, d.f.(Q)=9, I=0.000, P=0.750. CONCLUSION In this meta-analysis, we confirm the observation of decreased ERβ expression in CRC. Our results support the hypothesis of ERβ being a tumor-suppressor gene in the large bowel, and the ERβ protein protects against carcinogenesis and development of CRC when activated by estrogen. Further studies are needed to examine the potential of selective/specific ligands to activate ERβ without the side effects found with estrogen and without activating ERα. SUMMARY In this meta-analysis, we looked at studies that investigated the relationship between CRC and ERβ expression in the tumor and normal mucosa of CRC patients. English medical literature searches were performed for studies comparing ERβ expression in the cancer and normal colonic mucosa in patients with CRC. Meta-analysis was carried out, pooled odds ratios were calculated, and ERβ expression was compared in individual studies.
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34
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Feitelson MA, Arzumanyan A, Kulathinal RJ, Blain SW, Holcombe RF, Mahajna J, Marino M, Martinez-Chantar ML, Nawroth R, Sanchez-Garcia I, Sharma D, Saxena NK, Singh N, Vlachostergios PJ, Guo S, Honoki K, Fujii H, Georgakilas AG, Bilsland A, Amedei A, Niccolai E, Amin A, Ashraf SS, Boosani CS, Guha G, Ciriolo MR, Aquilano K, Chen S, Mohammed SI, Azmi AS, Bhakta D, Halicka D, Keith WN, Nowsheen S. Sustained proliferation in cancer: Mechanisms and novel therapeutic targets. Semin Cancer Biol 2015; 35 Suppl:S25-S54. [PMID: 25892662 PMCID: PMC4898971 DOI: 10.1016/j.semcancer.2015.02.006] [Citation(s) in RCA: 464] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 02/08/2023]
Abstract
Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.
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Affiliation(s)
- Mark A Feitelson
- Department of Biology, Temple University, Philadelphia, PA, United States.
| | - Alla Arzumanyan
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Rob J Kulathinal
- Department of Biology, Temple University, Philadelphia, PA, United States
| | - Stacy W Blain
- Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, NY, United States
| | - Randall F Holcombe
- Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, United States
| | - Jamal Mahajna
- MIGAL-Galilee Technology Center, Cancer Drug Discovery Program, Kiryat Shmona, Israel
| | - Maria Marino
- Department of Science, University Roma Tre, V.le G. Marconi, 446, 00146 Rome, Italy
| | - Maria L Martinez-Chantar
- Metabolomic Unit, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain
| | - Roman Nawroth
- Department of Urology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Isidro Sanchez-Garcia
- Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Salamanca, Spain
| | - Dipali Sharma
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Neeraj K Saxena
- Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, United States
| | - Neetu Singh
- Tissue and Cell Culture Unit, CSIR-Central Drug Research Institute, Council of Scientific & Industrial Research, Lucknow, India
| | | | - Shanchun Guo
- Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, GA, United States
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara 634-8521, Japan
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Elena Niccolai
- Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - S Salman Ashraf
- Department of Chemistry, College of Science, UAE University, Al-Ain, United Arab Emirates
| | - Chandra S Boosani
- Department of BioMedical Sciences, Creighton University, Omaha, NE, United States
| | - Gunjan Guha
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy
| | - Sophie Chen
- Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey GU2 7YG, United Kingdom
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - Asfar S Azmi
- Department of Pathology, Karmonas Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - Dipita Bhakta
- School of Chemical and Bio Technology, SASTRA University, Thanjavur, India
| | - Dorota Halicka
- Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, UK
| | - Somaira Nowsheen
- Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States
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Abstract
Bisphenol A (BPA) exposure has been associated with serious endocrine-disrupting effects in humans and wildlife. Toxicological and epidemiological studies evidenced that BPA increases body mass index and disrupts normal cardiovascular physiology by interfering with endogenous hormones in rodents, nonhuman primates, and cell culture test systems. The BPA concentration derived from these experiments were used by government regulatory agencies to determine the safe exposure levels of BPA in humans. However, accumulating literature in vivo and in vitro indicate that at concentrations lower than that reported in toxicological studies, BPA could elicit a different endocrine-disrupting capacity. To further complicate this picture, BPA effects rely on several and diverse mechanisms that converge upon endocrine and reproductive systems. If all or just few of these mechanisms concur to the endocrine-disrupting potential of low doses of BPA is at present still unclear. Thus, taking into account that the incidence and/or prevalence of health problems associated with endocrine disruption have increased worldwide, the goal of the present review is to give an overview of the many mechanisms of BPA action in order to decipher whether different mechanisms are at the root of the effect of low dose of BPA on endocrine system.
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Affiliation(s)
| | | | - Maria Marino
- Department of Science, Roma Tre University, Roma, Italy; INBB-National Laboratory of Gender and Endocrine Disruptors, Roma, Italy
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36
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Protein S-palmitoylation and cancer. Biochim Biophys Acta Rev Cancer 2015; 1856:107-20. [PMID: 26112306 DOI: 10.1016/j.bbcan.2015.06.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 06/16/2015] [Accepted: 06/21/2015] [Indexed: 12/16/2022]
Abstract
Protein S-palmitoylation is a reversible posttranslational modification of proteins with fatty acids, an enzymatic process driven by a recently discovered family of protein acyltransferases (PATs) that are defined by a conserved catalytic domain characterized by a DHHC sequence motif. Protein S-palmitoylation has a prominent role in regulating protein location, trafficking and function. Recent studies of DHHC PATs and their functional effects have demonstrated that their dysregulation is associated with human diseases, including schizophrenia, X-linked mental retardation, and Huntington's Disease. A growing number of reports indicate an important role for DHHC proteins and their substrates in tumorigenesis. Whereas DHHC PATs comprise a family of 23 enzymes in humans, a smaller number of enzymes that remove palmitate have been identified and characterized as potential therapeutic targets. Here we review current knowledge of the enzymes that mediate reversible palmitoylation and their cancer-associated substrates and discuss potential therapeutic applications.
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37
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Giromini C, Baldi A, Fusi E, Rebucci R, Purup S. Effect of growth factors, estradiol 17-β, and short chain fatty acids on the intestinal HT29-MTX cells : Growth factors and SCFAs effects on intestinal E12 cells. Cell Biol Toxicol 2015; 31:199-209. [PMID: 26072051 DOI: 10.1007/s10565-015-9304-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 06/01/2015] [Indexed: 02/06/2023]
Abstract
Peptides growth factors, hormones, and short chain fatty acids (SCFAs) are constantly in contact with the human bowel when secreted by gland or ingested by food, as milk and colostrum, or, as in the case of SCFAs, produced by fermentation processes. This study considers the effect of growth factors, estradiol 17-β, and SCFAs on the metabolic activity and proliferation of undifferentiated HT29-MTX-E12 (E12) cells. In particular, the aim of the present study was the characterization of the human intestinal cell line E12 for its suitability as an in vitro intestinal model for cell-nutrient interaction studies. The effect of insulin-like growth factors (IGF)-I, epidermal growth factors (EGF), transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), estradiol 17-β and butyrate, propionate, and acetate was assessed on metabolic activity and proliferation of E12 cells using AlamarBlue(TM) assay and PicoGreen® assay, respectively. IGF-I and estradiol 17-β significantly (P < 0.05; P < 0.001) increased both metabolic activity and proliferation in a concentration-dependent manner, whereas TGF-α, at the concentration of 1 ng/mL, significantly (P < 0.05) reduced the metabolic activity of the cells. Further, a dose-dependent inhibition of cell metabolic activity was detected in the presence of all SCFAs tested. Butyrate showed to be the most active in the inhibition of E12 metabolic activity and its effect was enhanced by the presence of propionate and acetate. E12 cells, in undifferentiated state, showed to be a suitable in vitro model for cell-nutrient interaction studies, providing an opportunity to examine the potential role of growth factors, hormones and SCFAs in the regulation of the intestinal cell viability.
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Affiliation(s)
- Carlotta Giromini
- Department of Health, Animal Science, and Food Safety, University of Milan, via Trentacoste 2, 20134, Milan, Italy
| | - Antonella Baldi
- Department of Health, Animal Science, and Food Safety, University of Milan, via Trentacoste 2, 20134, Milan, Italy.
| | - Eleonora Fusi
- Department of Health, Animal Science, and Food Safety, University of Milan, via Trentacoste 2, 20134, Milan, Italy
| | - Raffaella Rebucci
- Department of Health, Animal Science, and Food Safety, University of Milan, via Trentacoste 2, 20134, Milan, Italy
| | - Stig Purup
- Department of Animal Science, Faculty of Science and Technology, Aarhus University, Blichers Allè 20, PO BOX 50, 8830, Tjele, Denmark
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38
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Fiocchetti M, Camilli G, Acconcia F, Leone S, Ascenzi P, Marino M. ERβ-dependent neuroglobin up-regulation impairs 17β-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury. J Steroid Biochem Mol Biol 2015; 149:128-37. [PMID: 25683270 DOI: 10.1016/j.jsbmb.2015.02.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 01/20/2015] [Accepted: 02/10/2015] [Indexed: 11/18/2022]
Abstract
Besides other mechanism(s) 17β-estradiol (E2) facilitates neuronal survival by increasing, via estrogen receptor β (ERβ), the levels of neuroglobin (NGB) an anti-apoptotic protein. In contrast, E2 could exert protective effects in cancer cells by activating apoptosis when the ERβ level prevails on that of ERα as in colon cancer cell lines. These apparently contrasting results raise the possibility that E2-induced NGB up-regulation could regulate the ERβ activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in non-neuronal cells. Here, human colorectal adenocarcinoma cell line (DLD-1) that only expresses ERβ and HeLa cells transiently transfected with ERβ encoding vector has been used to verify this hypothesis. In addition, neuroblastoma SK-N-BE cells were used as positive control. Surprisingly, E2 also induced NGB up-regulation, in a dose- and time-dependent manner, in DLD-1 cells. The ERβ-mediated activation of p38/MAPK was necessary for this E2 effect. E2 induced NGB re-allocation in mitochondria where, subsequently to an oxidative stress injury (i.e., 100μM H2O2), NGB interacted with cytochrome c preventing its release into the cytosol and the activation of an apoptotic cascade. As a whole, these results demonstrate that E2-induced NGB up-regulation could act as an oxidative stress sensor, which does not oppose to the pro-apoptotic E2 effect in ERβ-containing colon cancer cells unless a rise of oxidative stress occurs. These results support the concept that oxidative stress plays a critical role in E2-induced carcinogenesis and further open an important scenario to develop novel therapeutic strategies that target NGB against E2-related cancers.
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Affiliation(s)
- Marco Fiocchetti
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - Giulia Camilli
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - Filippo Acconcia
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - Stefano Leone
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - Paolo Ascenzi
- Interdepartmental Laboratory of Electron Microscopy, Roma Tre University, Via della Vasca Navale 79, I-00146 Roma, Italy
| | - Maria Marino
- Department of Science, Roma Tre University, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
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Caiazza F, Ryan EJ, Doherty G, Winter DC, Sheahan K. Estrogen receptors and their implications in colorectal carcinogenesis. Front Oncol 2015; 5:19. [PMID: 25699240 PMCID: PMC4313613 DOI: 10.3389/fonc.2015.00019] [Citation(s) in RCA: 144] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 01/16/2015] [Indexed: 12/31/2022] Open
Abstract
Upon binding their cognate receptors, ERα (ESR1) and ERβ (ESR2), estrogens activate intracellular signaling cascades that have important consequences for cellular behavior. Historically linked to carcinogenesis in reproductive organs, estrogens have also been implicated in the pathogenesis of different cancer types of non-reproductive tissues including the colon. ERβ is the predominant estrogen receptor expressed in both normal and malignant colonic epithelium. However, during colon cancer progression, ERβ expression is lost, suggesting that estrogen signaling may play a role in disease progression. Estrogens may in fact exert an anti-tumor effect through selective activation of pro-apoptotic signaling mediated by ERβ, inhibition of inflammatory signals and modulation of the tumor microenvironment. In this review, we analyze the estrogen pathway as a possible therapeutic avenue in colorectal cancer, we report the most recent experimental evidence to explain the cellular and molecular mechanisms of estrogen-mediated protection against colorectal tumorigenesis, and we discuss future challenges and potential avenues for targeted therapy.
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Affiliation(s)
- Francesco Caiazza
- Centre for Colorectal Disease, Saint Vincent's University Hospital , Dublin , Ireland ; School of Medicine and Medical Science, University College , Dublin , Ireland
| | - Elizabeth J Ryan
- Centre for Colorectal Disease, Saint Vincent's University Hospital , Dublin , Ireland ; School of Medicine and Medical Science, University College , Dublin , Ireland
| | - Glen Doherty
- Centre for Colorectal Disease, Saint Vincent's University Hospital , Dublin , Ireland ; School of Medicine and Medical Science, University College , Dublin , Ireland
| | - Desmond C Winter
- Centre for Colorectal Disease, Saint Vincent's University Hospital , Dublin , Ireland ; Department of Surgery, St. Vincent's University Hospital, Elm Park , Dublin , Ireland
| | - Kieran Sheahan
- Centre for Colorectal Disease, Saint Vincent's University Hospital , Dublin , Ireland ; School of Medicine and Medical Science, University College , Dublin , Ireland ; Department of Pathology, Saint Vincent's University Hospital , Dublin , Ireland
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Klaus C, Schneider U, Hedberg C, Schütz AK, Bernhagen J, Waldmann H, Gassler N, Kaemmerer E. Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity. World J Gastroenterol 2014; 20:14855-14864. [PMID: 25356045 PMCID: PMC4209548 DOI: 10.3748/wjg.v20.i40.14855] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 05/10/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of acyl-CoA synthetase 5 (ACSL5) activity in Wnt signaling in intestinal surface epithelia.
METHODS: Several cell lines were used to investigate the ACSL5-dependent expression and synthesis of Wnt2B, a mitochondrially expressed protein of the Wnt signaling family. Wnt activity was functionally assessed with a luciferase reporter assay. ACSL5-related biochemical Wnt2B modifications were investigated with a modified acyl-exchange assay. The findings from the cell culture models were verified using an Apcmin/+ mouse model as well as normal and neoplastic diseased human intestinal tissues.
RESULTS: In the presence of ACSL5, Wnt2B was unable to translocate into the nucleus and was enriched in mitochondria, which was paralleled by a significant decrease in Wnt activity. ACSL5-dependent S-palmitoylation of Wnt2B was identified as a molecular reason for mitochondrial Wnt2B accumulation. In cell culture systems, a strong relation of ACSL5 expression, Wnt2B palmitoylation, and degree of malignancy were found. Using normal mucosa, the association of ACSL5 and Wnt2B was seen, but in intestinal neoplasias the mechanism was only rudimentarily observed.
CONCLUSION: ACSL5 mediates antiproliferative activities via Wnt2B palmitoylation with diminished Wnt activity. The molecular pathway is probably relevant for intestinal homeostasis, overwhelmed by other pathways in carcinogenesis.
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Ferrucci A, Leboffe L, Agamennone M, Di Pizio A, Fiocchetti M, Marino M, Ascenzi P, Luisi G. Ac-tLeu-Asp-H is the minimal and highly effective human caspase-3 inhibitor: biological and in silico studies. Amino Acids 2014; 47:153-62. [DOI: 10.1007/s00726-014-1855-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 10/09/2014] [Indexed: 10/24/2022]
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Fiocchetti M, Nuzzo MT, Totta P, Acconcia F, Ascenzi P, Marino M. Neuroglobin, a pro-survival player in estrogen receptor α-positive cancer cells. Cell Death Dis 2014; 5:e1449. [PMID: 25299774 PMCID: PMC4237245 DOI: 10.1038/cddis.2014.418] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 07/28/2014] [Accepted: 08/25/2014] [Indexed: 11/09/2022]
Abstract
Recently, we reported that human neuroglobin (NGB) is a new player in the signal transduction pathways that lead to 17β-estradiol (E2)-induced neuron survival. Indeed, E2 induces in neuron mitochondria the enhancement of NGB level, which in turn impairs the activation of a pro-apoptotic cascade. Nowadays, the existence of a similar pathway activated by E2 in non-neuronal cells is completely unknown. Here, the role of E2-induced NGB upregulation in tumor cells is reported. E2 induced the upregulation of NGB in a dose- and time-dependent manner in MCF-7, HepG2, SK-N-BE, and HeLa cells transfected with estrogen receptor α (ERα), whereas E2 was unable to modulate the NGB expression in the ERα-devoid HeLa cells. Both transcriptional and extranuclear ERα signals were required for the E2-dependent upregulation of NGB in MCF-7 and HepG2 cell lines. E2 stimulation modified NGB intracellular localization, inducing a significant reduction of NGB in the nucleus with a parallel increase of NGB in the mitochondria in both HepG2 and MCF-7 cells. Remarkably, E2 pretreatment did not counteract the H2O2-induced caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, as well as Bcl-2 overexpression in MCF-7 and HepG2 cells in which NGB was stably silenced by using shRNA lentiviral particles, highlighting the pivotal role of NGB in E2-induced antiapoptotic pathways in cancer cells. Present results indicate that the E2-induced NGB upregulation in cancer cells could represent a defense mechanism of E2-related cancers rendering them insensitive to oxidative stress. As a whole, these data open new avenues to develop therapeutic strategies against E2-related cancers.
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Affiliation(s)
- M Fiocchetti
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - M T Nuzzo
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - P Totta
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - F Acconcia
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
| | - P Ascenzi
- Interdepartmental Laboratory of Electron Microscopy, University Roma Tre, Via della Vasca Navale 79, I-00146 Roma, Italy
| | - M Marino
- Department of Science, University Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy
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López-Calderero I, Carnero A, Astudillo A, Palacios J, Chaves M, Benavent M, Limón ML, Garcia-Carbonero R. Prognostic relevance of estrogen receptor-α Ser167 phosphorylation in stage II-III colon cancer patients. Hum Pathol 2014; 45:2437-46. [PMID: 25283475 DOI: 10.1016/j.humpath.2014.08.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 07/22/2014] [Accepted: 08/05/2014] [Indexed: 02/07/2023]
Abstract
Preclinical and clinical data suggest a protective role for estrogens on colon cancer (CRC) risk. estrogen receptor (ER) β is the prevalent ER in normal colonic mucosa, whereas its expression is significantly reduced in CRC. An increased ERα/β ratio has been documented in colon carcinomas and is associated with increased proliferation and decreased apoptosis. The aim of our study was to evaluate the expression of activated ERα and its prognostic implications in patients with stage II-III CRC. Phospho-ERα(Ser167) (pERα(Ser167)) expression was assessed by immunohistochemistry in 218 CRC paraffin-embedded tumor samples. A high pERα(Ser167) expression was more commonly observed in women, older patients, and patients with high baseline glucose levels. This higher pERα(Ser167) expression was associated with decreased 5-year disease-free interval (DFI; 66% versus 78%, P = .07) and overall survival (65% versus 73%, P = .46). The negative impact of high pERα(Ser167) expression on DFI was particularly significant (P < .05) in women (85% versus 60%), young (82% versus 61%), nondiabetic (85% versus 66%), and stage II patients (86% versus 72% and low versus high pERα(Ser167), respectively). Multivariate analysis confirmed that pERα(Ser167) score was a significant prognostic factor for both DFI and overall survival, independent of sex, age, glucose levels, tumor stage, bowel obstruction/perforation, or adjuvant chemotherapy. These findings illustrate the relevance of estrogen pathways in colon cancer biology and may provide novel therapeutic avenues to be explored in this context.
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Affiliation(s)
- Iker López-Calderero
- Instituto de Biomedicina de Sevilla (IBIS), HUVR/CSIC/Universidad de Sevilla, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain; Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), HUVR/CSIC/Universidad de Sevilla, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain
| | - Aurora Astudillo
- Department of Pathology, Hospital Central de Asturias, Asturias, 33006, Spain
| | - José Palacios
- Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, 41013, Spain
| | - Manuel Chaves
- Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain
| | - Marta Benavent
- Instituto de Biomedicina de Sevilla (IBIS), HUVR/CSIC/Universidad de Sevilla, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain; Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain
| | - María L Limón
- Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain
| | - Rocio Garcia-Carbonero
- Instituto de Biomedicina de Sevilla (IBIS), HUVR/CSIC/Universidad de Sevilla, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain; Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Center affiliated to the Red Temática de Investigación Cooperativa en Cancer (RTICC), Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, 41013, Spain.
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Pellegrini M, Bulzomi P, Lecis M, Leone S, Campesi I, Franconi F, Marino M. Endocrine disruptors differently influence estrogen receptor β and androgen receptor in male and female rat VSMC. J Cell Physiol 2014; 229:1061-8. [PMID: 24347325 DOI: 10.1002/jcp.24530] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2013] [Accepted: 12/11/2013] [Indexed: 12/18/2022]
Abstract
Sex steroid hormones differently control the major physiological processes in male and female organisms. In particular, their effects on vascular smooth muscle cells (VSMCs) migration are at the root of sex/gender-related differences reported in the cardiovascular system. Several exogenous substances, defined endocrine disruptor chemicals (EDCs), could interfere with these androgen and estrogen effects; however, the sex/gender-related susceptibility of VSMC motility to EDCs is completely unknown. Here, the effect of naturally occurring (naringenin, Nar) and synthetic (bisphenol A, BPA) EDCs on male and female VSMC motility has been evaluated. 17β-estradiol (E2, 0.1 nM-1 µM) induced a dose-dependent inhibition of motility in female-derived VSMC. In contrast, neither dihydrotestosterone (DHT, 0.01-100 nM) nor the common precursor of sex steroid hormones, testosterone (Tes, 0.01-100 nM) modified male-derived VSMC motility. Estrogen receptor (ER) β subtype-dependent activation of p38 was necessary for the E2 effect on cell motility. High BPA concentration prevented E2 effects in female-derived cells being without any effect in male-derived cells. Nar mimicked E2 effects on female-derived cells even in the presence of E2 or BPA. Intriguingly, Nar also inhibited the male-derived VSMC mobility. This latter effect was prevented by ERβ inhibitor, but not by the androgen receptor (AR) inhibitor. As a whole, ERβ-dependent signals in VSMC results more susceptible to the impact of EDCs than AR signals suggesting a possible high and overall susceptibility of female to EDCs. However, several male-derived cells, including VSMC, express ERβ, which could also serve as target of EDC disruption in male organisms.
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Yeste-Velasco M, Mao X, Grose R, Kudahetti SC, Lin D, Marzec J, Vasiljević N, Chaplin T, Xue L, Xu M, Foster JM, Karnam SS, James SY, Chioni AM, Gould D, Lorincz AT, Oliver RTD, Chelala C, Thomas GM, Shipley JM, Mather SJ, Berney DM, Young BD, Lu YJ. Identification of ZDHHC14 as a novel human tumour suppressor gene. J Pathol 2014; 232:566-77. [PMID: 24407904 DOI: 10.1002/path.4327] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2013] [Revised: 12/20/2013] [Accepted: 01/03/2014] [Indexed: 01/19/2023]
Abstract
Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene, ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased at both RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. In addition to our findings of genetic and protein expression changes in clinical samples, inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent apoptotic pathway and heterozygous knockout of ZDHHC14 increased [CORRECTED] cell colony formation ability. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus, we have identified a novel tumour suppressor gene that is commonly down-regulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer.
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Affiliation(s)
- Marc Yeste-Velasco
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
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Marino M. Xenoestrogens challenge 17β-estradiol protective effects in colon cancer. World J Gastrointest Oncol 2014; 6:67-73. [PMID: 24653796 PMCID: PMC3955780 DOI: 10.4251/wjgo.v6.i3.67] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/10/2014] [Accepted: 02/18/2014] [Indexed: 02/05/2023] Open
Abstract
Several epidemiological, cellular, and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities, typical of Westernized societies, in the pathogenesis of numerous diseases including cancer. Nonetheless this information, the design and execution of studies on endocrine disruptors are not yet cognizant that the specific actions of individual hormones often change with development and ageing, they may be different in males and females and may be mediated by different receptors isoforms expressed in different tissues or at different life stages. These statements are particularly true when assessing the hazard of endocrine disruptors against 17β-estradiol (E2) actions in that this hormone is crucial determinant of sex-related differences in anatomical, physiological, and behavioral traits which characterize male and female physiology. Moreover, E2 is also involved in carcinogenesis. The oncogenic effects of E2 have been investigated extensively in breast and ovarian cancers where hormone-receptor modulators are now an integral part of targeted treatment. Little is known about the E2 preventive signalling in colorectal cancer, although this disease is more common in men than women, the difference being more striking amongst pre-menopausal women and age-matched men. This review aims to dissect the role and action mechanisms of E2 in colorectal cancer evaluating the ability of estrogen disruptors (i.e., xenoestrogens) in impair these E2 actions. Data discussed here lead to define the possible role of xenoestrogens in the impairment and/or activation of E2 signals important for colorectal cancer prevention.
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Manavathi B, Dey O, Gajulapalli VNR, Bhatia RS, Bugide S, Kumar R. Derailed estrogen signaling and breast cancer: an authentic couple. Endocr Rev 2013; 34:1-32. [PMID: 22947396 PMCID: PMC3565105 DOI: 10.1210/er.2011-1057] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2011] [Accepted: 07/09/2012] [Indexed: 02/06/2023]
Abstract
Estrogen or 17β-estradiol, a steroid hormone, plays a critical role in the development of mammary gland via acting through specific receptors. In particular, estrogen receptor-α (ERα) acts as a transcription factor and/or a signal transducer while participating in the development of mammary gland and breast cancer. Accumulating evidence suggests that the transcriptional activity of ERα is altered by the action of nuclear receptor coregulators and might be responsible, at least in part, for the development of breast cancer. In addition, this process is driven by various posttranslational modifications of ERα, implicating active participation of the upstream receptor modifying enzymes in breast cancer progression. Emerging studies suggest that the biological outcome of breast cancer cells is also influenced by the cross talk between microRNA and ERα signaling, as well as by breast cancer stem cells. Thus, multiple regulatory controls of ERα render mammary epithelium at risk for transformation upon deregulation of normal homeostasis. Given the importance that ERα signaling has in breast cancer development, here we will highlight how the activity of ERα is controlled by various regulators in a spatial and temporal manner, impacting the progression of the disease. We will also discuss the possible therapeutic value of ERα modulators as alternative drug targets to retard the progression of breast cancer.
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Affiliation(s)
- Bramanandam Manavathi
- Department of Biochemistry, School of Life Sciences, Gachibowli, Prof. CR Rao Road, University of Hyderabad, Hyderabad 500046, India.
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Kampa M, Pelekanou V, Notas G, Stathopoulos EN, Castanas E. The estrogen receptor: two or more molecules, multiple variants, diverse localizations, signaling and functions. Are we undergoing a paradigm-shift as regards their significance in breast cancer? Hormones (Athens) 2013; 12:69-85. [PMID: 23624133 DOI: 10.1007/bf03401288] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Marilena Kampa
- Department of Experimental Endocrinology, University of Crete, School of Medicine, Heraklion, Crete, Greece
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Estrogen in obesity-associated colon cancer: friend or foe? Protecting postmenopausal women but promoting late-stage colon cancer. Cancer Causes Control 2012; 23:1767-73. [PMID: 23011535 DOI: 10.1007/s10552-012-0066-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Accepted: 09/11/2012] [Indexed: 12/12/2022]
Abstract
Obesity is associated with the increased incidence of colon cancer. Many cancer risk factors have been identified including increased blood levels of insulin, leptin, interleukin-6, interleukin-17, tumor necrosis factor-alpha, and decreased blood levels of adiponectin. However, the role of blood levels of estrogen in obesity-associated colon cancer is controversial. Evidence showed that obesity affected men more strongly than women in the carcinogenesis of colon cancer, indicating protective effect of estrogen which is increased in obesity. However, an epidemiological study has also shown that endogenous estradiol level is an independent risk factor for colon cancer, positively associated with colon cancer after normalizing insulin, IGF-1. The controversial opinions may be caused by different effects of ER-alpha and ER-beta. ER-alpha can increase colon cancer cell proliferation and increase cancer incidence. ER-beta has the opposite effect to ER-alpha, and it causes apoptosis of colon cancer cells. The normal colonocytes mainly express ER-beta. Therefore, increased estrogen in obesity may have protective effect via ER-beta in obesity-associated colon cancer. However, with the development of colon cancer, ER-alpha is increased and ER-beta is decreased. In the late stage of colon cancer, estrogen may promote cancer development via ER-alpha. The different effects and expression of ER-alpha and ER-beta may explain the different results observed in several epidemiological studies as well as several animal experiments. Therefore, manipulation of estrogen-caused signal pathways to inhibit ER-alpha and stimulate ER-beta may have preventive and therapeutic effect for obesity-associated colon cancer.
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Marino M, Pellegrini M, La Rosa P, Acconcia F. Susceptibility of estrogen receptor rapid responses to xenoestrogens: Physiological outcomes. Steroids 2012; 77:910-7. [PMID: 22410438 DOI: 10.1016/j.steroids.2012.02.019] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 02/13/2012] [Accepted: 02/24/2012] [Indexed: 02/06/2023]
Abstract
17β-Estradiol (E2) binding induces rapid modification in the conformation of its cognate receptors (i.e., ERα and ERβ). These allosteric changes allow the association of ERs with cell specific transcriptional cofactors, thus determining cellular contexts specific variations in gene expression. In addition, E2-ER complexes could also interact with membrane and cytosolic signal molecules triggering extra-nuclear signalling pathways. The synergy between these mechanisms is necessary for E2-induced pleiotropic actions in target tissues. Besides E2, the ER ligand binding domains can accommodate many other natural and synthetic ligands. Several of these compounds act as agonist or antagonist of ER transcriptional activity due to their ability to modify the interactions between ERs and transcriptional co-regulators. However, the ability of natural or manmade ER ligands to affect the extra-nuclear interactions of the ERs has been rarely evaluated. Here, the ability of two diet-derived flavonoids (i.e., naringenin and quercetin) and of the synthetic food-contaminant bisphenol A to modulate specifically ER extra-nuclear signalling pathways will be reported. All the tested compounds bind to both ER subtypes even if lesser than E2 activating divergent signal transduction pathways. In fact, in the presence of ERα, both naringenin and quercetin decouple ERα activities by specifically interfering with ERα membrane initiating signals. On the other hand, bisphenol A, but not flavonoids, maintains ERβ at the membrane thus impairing the activation of the downstream kinases. As a whole, extra-nuclear ER signals are highly susceptible to different ligands that, by unbalancing E2-induced cell functions drive cells to different functional endpoints.
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Affiliation(s)
- Maria Marino
- Department of Biology, University Roma TRE, viale G. Marconi, 446, I-00146 Rome, Italy.
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