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Murphy A, Shyanti RK, Mishra M. Targeting obesity, metabolic syndrome, and prostate cancer: GLP-1 agonists as emerging therapeutic agents. Discov Oncol 2025; 16:258. [PMID: 40024963 PMCID: PMC11872791 DOI: 10.1007/s12672-025-01878-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 02/03/2025] [Indexed: 03/04/2025] Open
Abstract
Prostate cancer (PCa) is known as the second most common cancer and has one of the highest incidences among male cancers in the United States. In addition, obesity and metabolic syndrome are a rising and continuous issue in the United States, with 41.9% of individuals as obese. The importance of highlighting these figures is the possibility of PCa having a progressive relationship with obesity and metabolic syndromes. The drugs developed for treating obesity and diabetes pose an exciting possibility of therapeutic application for cancer in efforts to relieve the population's rising numbers. Although this connection has not been established in detail, there are some PCa key biomarkers, and their interactions with metabolic products found in obese, diabetic, and PCa patients can provide good starting points for further investigation. One of the significant links between PCa, obesity, and metabolic disease may be due to insulin metabolism. A downstream target identified that could be the link between PCa, metabolic syndromes, and obesity is the forkhead box C2 (FOXC2). FOXC2 has been known to inhibit some insulin-resistant genes and cause the proliferation of PCa. The relationships of FOXC2, insulin resistance, and GLP-1 receptor agonists as potential therapeutic applications have not been thoroughly explored. This review covers a broad relationship of PCa, obesity, metabolic syndromes, possible drugs, and therapeutic targets.
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Affiliation(s)
- Azura Murphy
- Cancer Research Center, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36104, USA
| | - Ritis Kumar Shyanti
- Cancer Research Center, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36104, USA
| | - Manoj Mishra
- Cancer Research Center, Department of Biological Sciences, Alabama State University, Montgomery, AL, 36104, USA.
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Lee CM, Fang S. Fat Biology in Triple-Negative Breast Cancer: Immune Regulation, Fibrosis, and Senescence. J Obes Metab Syndr 2023; 32:312-321. [PMID: 38014425 PMCID: PMC10786212 DOI: 10.7570/jomes23044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/18/2023] [Accepted: 11/21/2023] [Indexed: 11/29/2023] Open
Abstract
Obesity, now officially recognized as a disease requiring intervention, has emerged as a significant health concern due to its strong association with elevated susceptibility to diverse diseases and various types of cancer, including breast cancer. The link between obesity and cancer is intricate, with obesity exerting a significant impact on cancer recurrence and elevated mortality rates. Among the various subtypes of breast cancer, triple-negative breast cancer (TNBC) is the most aggressive, accounting for 15% to 20% of all cases. TNBC is characterized by low expression of estrogen receptors and progesterone receptors as well as the human epidermal growth factor 2 receptor protein. This subtype poses distinct challenges in terms of treatment response and exhibits strong invasiveness. Furthermore, TNBC has garnered attention because of its association with obesity, in which excess body fat and reduced physical activity have been identified as contributing factors to the increased incidence of this aggressive form of breast cancer. In this comprehensive review, the impact of obesity on TNBC was explored. Specifically, we focused on the three key mechanisms by which obesity affects TNBC development and progression: modification of the immune profile, facilitation of fibrosis, and initiation of senescence. By comprehensively examining these mechanisms, we illuminated the complex interplay between TNBC and obesity, facilitating the development of novel approaches for prevention, early detection, and effective management of this challenging disease.
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Affiliation(s)
- Chae Min Lee
- Graduate School of Medical Science, Brain Korea 2 Project, Yonsei University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Sungsoon Fang
- Graduate School of Medical Science, Brain Korea 2 Project, Yonsei University College of Medicine, Seoul, Korea
- Department of Biomedical Sciences, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Korea
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
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3
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Wang X, Guo L, Liu G, Liu T. Leptin Mediates Prostate Stromal Cell Proliferation, Smooth Muscle Contraction, and Mitochondrial Function in Benign Prostate Hyperplasia. Diabetes Metab Syndr Obes 2023; 16:3261-3273. [PMID: 37876983 PMCID: PMC10591609 DOI: 10.2147/dmso.s420258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/13/2023] [Indexed: 10/26/2023] Open
Abstract
Introduction Leptin is a metabolic peptide hormone produced by adipocytes, with proven roles in proliferation of prostate cancer cells and of prostate cells in animal models of benign prostatic hyperplasia (BPH). Thus, the role of leptin as a molecular link connecting BPH and lower urinary tract symptoms (LUTS) suggestive of BPH with metabolic symptoms appears feasible but is still unknown. In fact, a connection between metabolic syndrome and BPH is becoming increasingly evident from epidemiologic studies. Key factors of Lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH/LUTS) are increased prostate smooth muscle tone, and prostate enlargement. Here, we examined the effects of leptin on contraction of human prostate smooth muscle and on growth of stromal cells. Methods We performed microarray analysis to identify genes (fold change ≥ 1.5) associated with BPH/LUTS progression, such as those involved in proliferation, apoptosis, and mitochondrial metabolism, in rat prostate tissue (data from GSE129561). We then used electric field stimulation (EFS) to induce frequency-dependent, neurogenic contractions of human prostate strips, which were enhanced by leptin. We also examined the effect of leptin on human prostate stromal cells (WPMY-1) and found increased cell proliferation and viability upon exposure. To explore the underlying mechanism, we conducted mitochondrial stress assay using near-infrared (NIR) fluorescent dye and flow cytometry (FACS) analysis and observed reduced cellular apoptosis and preserved mitochondrial membrane potential (∆ψM) after leptin treatment. Results Microarray analysis reveals that leptin regulates prostate smooth muscle contraction and stromal cell proliferation, shedding new light on its involvement in BPH/LUTS pathogenesis and mitochondrial function. We found that leptin enhanced the proliferation rate of prostate stromal cells relative to the control group (0.67 ± 0.05 vs 0.54 ± 0.08, p-value= 0.024). Moreover, leptin (100 ng/mL) potentiated the frequency-dependent, neurogenic contractions of prostate strips elicited by EFS (p= 0.047 between leptin and control group). We also show that leptin treatment increased the mitochondrial membrane potential of prostate stromal cells and inhibited mitochondrial apoptosis. Discussion Our results indicate that leptin stimulates the contractility and proliferation of smooth muscle and stromal cells in the human prostate, implying a potential role for leptin in exacerbating BPH/LUTS in obese men. Leptin modulation may be a beneficial therapeutic strategy for patients with metabolic syndrome and BPH/LUTS. Further studies are warranted to elucidate the mechanisms and implications of the leptin system in BPH/LUTS.
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Affiliation(s)
- Xiaolong Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Linfa Guo
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
| | - Guiyong Liu
- Qianjiang Central Hospital of Hubei Province, Qianjiang, People’s Republic of China
| | - Tongzu Liu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China
- Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, Wuhan, People’s Republic of China
- Hubei Province Key Laboratory of Urinary System Diseases, Wuhan, People’s Republic of China
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Interplay between Prostate Cancer and Adipose Microenvironment: A Complex and Flexible Scenario. Int J Mol Sci 2022; 23:ijms231810762. [PMID: 36142673 PMCID: PMC9500873 DOI: 10.3390/ijms231810762] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 11/17/2022] Open
Abstract
Adipose tissue is part of the prostate cancer (PCa) microenvironment not only in the periprostatic area, but also in the most frequent metastatic sites, such as bone marrow and pelvic lymph nodes. The involvement of periprostatic adipose tissue (PPAT) in the aggressiveness of PCa is strongly suggested by numerous studies. Many molecules play a role in the reciprocal interaction between adipocytes and PCa cells, including adipokines, hormones, lipids, and also lipophilic pollutants stored in adipocytes. The crosstalk has consequences not only on cancer cell growth and metastatic potential, but also on adipocytes. Although most of the molecules released by PPAT are likely to promote tumor growth and the migration of cancer cells, others, such as the adipokine adiponectin and the n-6 or n-3 polyunsaturated fatty acids (PUFAs), have been shown to have anti-tumor properties. The effects of PPAT on PCa cells might therefore depend on the balance between the pro- and anti-tumor components of PPAT. In addition, genetic and environmental factors involved in the risk and/or aggressiveness of PCa, including obesity and diet, are able to modulate the interactions between PPAT and cancer cells and their consequences on the growth and the metastatic potential of PCa.
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Idris MKH, Hasham R, Ismail HF. Bioassay-Guided extraction of andrographis paniculata for intervention of in-vitro prostate cancer progression in metabolic syndrome environment. Daru 2022; 30:253-272. [PMID: 35922691 PMCID: PMC9715910 DOI: 10.1007/s40199-021-00414-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 08/17/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Metabolic syndrome (MetS) is a risk factor for prostate cancer (PCa) progression. Thus, this life-threatening disease demands a proactive treatment strategy. Andrographis paniculata (AP) is a promising candidate with various medicinal properties. However, the bioactivity of AP is influenced by its processing conditions especially the extraction solvent. OBJECTIVE In the present study, bioassay-guided screening technique was employed to identify the best AP extract in the management of MetS, PCa, and MetS-PCa co-disease in vitro. METHODS Five AP extracts by different solvent systems; APE1 (aqueous), APE2 (absolute methanol), APE3 (absolute ethanol), APE4 (40% methanol), and APE5 (60% ethanol) were screened through their phytochemical profile, in-vitro anti-cancer, anti-obese, and anti-hyperglycemic properties. The best extract was further tested for its potential in MetS-induced PCa progression. RESULTS APE2 contained the highest andrographolide (1.34 ± 0.05 mg/mL) and total phenolic content (8.85 ± 0.63 GAE/gDW). However, APE3 has the highest flavonoid content (11.52 ± 0.80 RE/gDW). APE2 was also a good scavenger of DPPH radicals (EC50 = 397.0 µg/mL). In cell-based assays, among all extracts, APE2 exhibited the highest antiproliferative activity (IC50 = 57.5 ± 11.8 µg/mL) on DU145 cancer cell line as well as on its migration activity. In in-vitro anti-obese study, all extracts significantly reduced lipid formation in 3T3-L1 cells. The highest insulin-sensitizing and -mimicking actions were exerted by both APE2 and APE3. Taken together, APE2 showed collectively good activity in the inhibition of PCa progression and MetS manifestation in vitro, compared to other extracts. Therefore, APE2 was further investigated for its potential to intervene DU145 progression induced with leptin (10-100 ng/mL) and adipocyte conditioned media (CM) (10% v/v). Interestingly, APE2 significantly diminished the progression of the cancer cell that has been pre-treated with leptin and CM through cell cycle arrest at S phase and induction of cell death. CONCLUSION In conclusion, AP extracts rich with andrographolide has the potential to be used as an alternative to ameliorate PCa progression induced by factors highly expressed in MetS.
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Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue. Cancers (Basel) 2022; 14:cancers14071679. [PMID: 35406450 PMCID: PMC8996963 DOI: 10.3390/cancers14071679] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary As overweight and obesity increase among the population worldwide, a parallel increase in the number of individuals diagnosed with prostate cancer was observed. There appears to be a relationship between both diseases where the increase in the mass of fat tissue can lead to inflammation. Such a state of inflammation could produce many factors that increase the aggressiveness of prostate cancer, especially if this inflammation occurred in the fat stores adjacent to the prostate. Another important observation that links obesity, fat tissue inflammation, and prostate cancer is the increased production of blood clotting factors. In this article, we attempt to explain the role of these latter factors in the effect of increased body weight on the progression of prostate cancer and propose new ways of treatment that act by affecting how these clotting factors work. Abstract The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.
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Kang N, Oh S, Kim SY, Ahn H, Son M, Heo SJ, Byun K, Jeon YJ. Anti-obesity effects of Ishophloroglucin A from the brown seaweed Ishige okamurae (Yendo) via regulation of leptin signal in ob/ob mice. ALGAL RES 2022. [DOI: 10.1016/j.algal.2021.102533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Kim JS, Galvão DA, Newton RU, Gray E, Taaffe DR. Exercise-induced myokines and their effect on prostate cancer. Nat Rev Urol 2021; 18:519-542. [PMID: 34158658 DOI: 10.1038/s41585-021-00476-y] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
Exercise is recognized by clinicians in the field of clinical oncology for its potential role in reducing the risk of certain cancers and in reducing the risk of disease recurrence and progression; yet, the underlying mechanisms behind this reduction in risk are not fully understood. Studies applying post-exercise blood serum directly to various types of cancer cell lines provide insight that exercise might have a role in inhibiting cancer growth via altered soluble and cell-free blood contents. Myokines, which are cytokines produced by muscle and secreted into the bloodstream, might offer multiple benefits to cellular metabolism (such as a reduction in insulin resistance, improved glucose uptake and reduced adiposity), and blood myokine levels can be altered with exercise. Alterations in the levels of myokines such as IL-6, IL-15, IL-10, irisin, secreted protein acidic risk in cysteine (SPARC), myostatin, oncostatin M and decorin might exert a direct inhibitory effect on cancer growth via inhibiting proliferation, promoting apoptosis, inducing cell-cycle arrest and inhibiting the epithermal transition to mesenchymal cells. The association of insulin resistance, hyperinsulinaemia and hyperlipidaemia with obesity can create a tumour-favourable environment; exercise-induced myokines can manipulate this environment by regulating adipose tissue and adipocytes. Exercise-induced myokines also have a critical role in increasing cytotoxicity and the infiltration of immune cells into the tumour.
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Affiliation(s)
- Jin-Soo Kim
- Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia.,School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Daniel A Galvão
- Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia. .,School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
| | - Robert U Newton
- Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia.,School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Elin Gray
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Dennis R Taaffe
- Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia.,School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
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Kim JH, Han IH, Shin SJ, Park SY, Chung HY, Ryu JS. Signaling Role of Adipocyte Leptin in Prostate Cell Proliferation Induced by Trichomonas vaginalis. THE KOREAN JOURNAL OF PARASITOLOGY 2021; 59:235-249. [PMID: 34218595 PMCID: PMC8255495 DOI: 10.3347/kjp.2021.59.3.235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 05/07/2021] [Indexed: 12/19/2022]
Abstract
Leptin is a type of adipokine mainly produced by adipocytes and reported to be overproduced in prostate cancer. However, it is not known whether it stimulates the proliferation of prostate cells. In this study, we investigated whether benign prostatic hyperplasia epithelial cells (BPH-1 cells) infected with Trichomonas vaginalis induced the proliferation of prostate cells via a leptin signaling pathway. To investigate the effect of crosstalk between adipocyte leptin and inflamed epithelial cell in proliferation of prostate cells, adipocytes 3T3-L1 cells were incubated in conditioned medium of BPH-1 cells infected with T. vaginalis (T. vaginalis-conditioned medium, TCM), and then the adipocyte-conditioned medium (ATCM) was identified to cause proliferation of prostate cells. BPH-1 cells incubated with live T. vaginalis released pro-inflammatory cytokines, and conditioned medium of these cells caused migration of adipocytes. When prostate stromal cells and BPH-1 cells were incubated with adipocyte conditioned medium containing leptin, their growth rates increased as did expression of the leptin receptor (known as OBR) and signaling molecules such as JAK2/STAT3, Notch and survivin. Moreover, blocking the OBR reduced this proliferation and the expression of leptin signaling molecules in response to ATCM. In conclusion, our findings show that inflamed BPH-1 cells infected with T. vaginalis induce the proliferation of prostate cells through leptin-OBR signaling. Therefore, it is likely that T. vaginalis contributes to prostate enlargement in BPH via adipocyte leptin released as a result of inflammation of the prostate.
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Affiliation(s)
- Jung-Hyun Kim
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul 04763, Korea.,Department of Biomedical Science, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea
| | - Ik-Hwan Han
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul 04763, Korea.,Department of Biomedical Science, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea
| | - Su-Jin Shin
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Korea
| | - Sung-Yul Park
- Department of Urology, Hanyang University College of Medicine, Seoul 04763, Korea
| | - Hyo-Yeoung Chung
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul 04763, Korea.,Department of Biomedical Science, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea
| | - Jae-Sook Ryu
- Department of Environmental Biology and Medical Parasitology, Hanyang University College of Medicine, Seoul 04763, Korea.,Department of Biomedical Science, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul 04763, Korea
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Mechanistic Insights into the Link between Obesity and Prostate Cancer. Int J Mol Sci 2021; 22:ijms22083935. [PMID: 33920379 PMCID: PMC8069048 DOI: 10.3390/ijms22083935] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 12/21/2022] Open
Abstract
Obesity is a pandemic of increasing worldwide prevalence. There is evidence of an association between obesity and the risk of prostate cancer from observational studies, and different biologic mechanisms have been proposed. The chronic low-level inflammation within the adipose tissue in obesity results in oxidative stress, activation of inflammatory cytokines, deregulation of adipokines signaling, and increased circulating levels of insulin and insulin-like growth factors (IGF). These mechanisms may be involved in epithelial to mesenchymal transformation into a malignant phenotype that promotes invasiveness, aggressiveness, and metastatic potential of prostate cancer. A thorough understanding of these mechanisms may be valuable in the development of effective prostate cancer prevention strategies and treatments. This review provides an overview of these mechanisms.
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Olea-Flores M, Juárez-Cruz JC, Zuñiga-Eulogio MD, Acosta E, García-Rodríguez E, Zacapala-Gomez AE, Mendoza-Catalán MA, Ortiz-Ortiz J, Ortuño-Pineda C, Navarro-Tito N. New Actors Driving the Epithelial-Mesenchymal Transition in Cancer: The Role of Leptin. Biomolecules 2020; 10:E1676. [PMID: 33334030 PMCID: PMC7765557 DOI: 10.3390/biom10121676] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/12/2020] [Accepted: 12/13/2020] [Indexed: 12/24/2022] Open
Abstract
Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial-mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer.
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Affiliation(s)
- Monserrat Olea-Flores
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Juan C. Juárez-Cruz
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Miriam D. Zuñiga-Eulogio
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Erika Acosta
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Eduardo García-Rodríguez
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
| | - Ana E. Zacapala-Gomez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (A.E.Z.-G.); (M.A.M.-C.); (J.O.-O.)
| | - Miguel A. Mendoza-Catalán
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (A.E.Z.-G.); (M.A.M.-C.); (J.O.-O.)
| | - Julio Ortiz-Ortiz
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (A.E.Z.-G.); (M.A.M.-C.); (J.O.-O.)
| | - Carlos Ortuño-Pineda
- Laboratorio de Ácidos Nucleicos y Proteinas, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico;
| | - Napoleón Navarro-Tito
- Laboratorio de Biología Celular del Cáncer, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Mexico; (M.O.-F.); (J.C.J.-C.); (M.D.Z.-E.); (E.A.); (E.G.-R.)
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Abstract
Obesity is associated with high-grade and advanced prostate cancer. While this association may be multi-factorial, studies suggest that obesity-induced inflammation may play a role in the progression of advanced prostate cancer. The microenvironment associated with obesity increases growth factors and pro-inflammatory cytokines which have been implicated mechanistically to promote invasion, metastasis, and androgen-independent growth. This review summarizes recent findings related to obesity-induced inflammation which may be the link to advanced prostate cancer. In addition, this review while introduce novel targets to mitigate prostate cancer metastasis to the bone. Specific emphasis will be placed on the role of the pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)α, and IL-1β.
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Affiliation(s)
- Armando Olivas
- Nutrition and Foods, Texas State University, San Marcos, Texas, USA
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Wu X, Long X, Yang C, Chen H, Sharkey C, Rashid K, Hu M, Liu Y, Huang Q, Chen Q, Hu J, Jiang H. Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model. J Cancer 2020; 11:6556-6564. [PMID: 33046976 PMCID: PMC7545683 DOI: 10.7150/jca.48413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Objective: Obesity resulting from high-fat diets has a close relationship with the morbidity and mortality associated with Prostate cancer (PCa) in males. The anti-cancer role of Icaritin (ICT, a traditional Chinese herbal medicine) has been reported in several types of cancer including PCa. Adipokines are novel adipocyte-specific secretory protein, which plays a key role in the development of various diseases including obesity, diabetes, atherosclerosis, and cancer. However, the function of ICT and the molecular mechanisms underlying its role in PCa regression through modulation of adipokines have not been studied. Here, we assessed the anti-cancer properties of ICT under the influence of human epidermal growth factor receptor type 2 (HER2) pathway modulating adipokines in obese PCa models. Materials and Methods: In this study, we used transgenic adenocarcinoma of mouse prostate (TRAMP), a well-established animal model for the study of PCa pathogenesis. All the animals were fed on a high-fat diet (HFD with 40% fat) and divided into two groups, one received ICT solution of 30 mg/kg body bwt (i.p) while the other group served as control without any ICT treatment. The mortality rate, tumor formation and fat ratio were assessed by histopathological and magnetic resonance analysis at different time points of 20th, 24th and 28th weeks. The protein expression of HER2 and serum levels of adipokines were measured using western blotting, IHC and multiplex immunoassays. The PCa grade in 12 TRAMP mice were longitudinally evaluated to visualize PCa development and progression upon post-surgery using PET/CT scanning. Results: We observed that ICT treatment significantly reduces the total mortality rate of TRAMP mice (p = 0.045) and the percentage of prostate intraepithelial neoplasia (PIN) or PCa (p = 0.029). Interestingly, significantly decreased levels of leptin (p = 0.006 @20th wk) and the elevated levels of adiponectin (p = 0.030 @20th wk) were observed in different subgroups upon ICT treatment in a time-dependent manner. In addition, a decrease level of HER2 (p = 0.032 @28th wk) and an elevated level of PEA3 (p = 0.014 @28th wk) were also detected in ICT treated group. The PET/CT-based imaging showed that ICT vs non-ICT treated mice had different standard uptake value and metastasis. Discussion and Conclusion: Our results showed potent anti-cancer properties of ICT through the modulation of adipokine secretion may alter the expression and activation of HER2 pathway as an alternative mechanism to prevent PCa progression. Altogether, our findings indicate that ICT could be a promising cancer preventive agent with the potential to target and eradicate tumor cells in obese PCa patients.
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Affiliation(s)
- Xiaobo Wu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Department of General Surgery, Division of Urology, Beth Isreal Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Xingbo Long
- Department of General Surgery, Division of Urology, Beth Isreal Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.,Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Chen Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Huan Chen
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Christina Sharkey
- Department of General Surgery, Division of Urology, Beth Isreal Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Khalid Rashid
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mengbo Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yufei Liu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qi Huang
- PET center, Huashan Hospital, Fudan University, Shanghai, China
| | - Qi Chen
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Jimeng Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China
| | - Haowen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, China.,Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.,National Clinical Research Center for Aging and Medicine, Fudan University, Shanghai, China
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14
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Kamel HFM, Nassir AM, Al Refai AA. Assessment of expression levels of leptin and leptin receptor as potential biomarkers for risk of prostate cancer development and aggressiveness. Cancer Med 2020; 9:5687-5696. [PMID: 32573960 PMCID: PMC7402836 DOI: 10.1002/cam4.3082] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 04/03/2020] [Accepted: 04/09/2020] [Indexed: 01/06/2023] Open
Abstract
Background Prostate cancer (PCa) is one of the most frequently diagnosed cancers worldwide. Despite the growing evidence associating obesity and adipokines, particularly leptin and its receptors, with cancer development and progression, it is still a debatable matter in PCa. Objectives We aimed to assess the role of leptin and its receptors as potential biomarkers for the risk of PCa development and aggressiveness. Methods In this study, 176 men were included and categorized according to an established histopathological diagnosis into three age‐ and BMI‐matched groups. The PCa group included 56 patients while the BPH group and the control group comprised 60 men each. Serum levels of total PSA (tPSA) were assessed by ELISA and mRNA expression levels of leptin and leptin receptors were assessed by RT‐PCR. Results Leptin and leptin receptor mRNA expression levels were significantly higher in PCa patients relative to BPH and to healthy control men. Both were overexpressed in PCa patients with aggressive and distantly metastasizing tumors compared to patients with confined tumors. Leptin receptor mRNA was an independent predictor of high Gleason score ≥ 7, distant metastasis, LN, and seminal vesicles invasion. Conclusion Leptin and its receptors are suggested to be potential biomarkers for PCa; leptin receptor mRNA might predict risk and aggressiveness of PCa.
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Affiliation(s)
- Hala Fawzy Mohamed Kamel
- Faculty of Medicine, Biochemistry Department, Umm Al-Qura University, Makkah, Saudi Arabia.,Faculty of Medicine, Medical Biochemistry Department, Ain Shams University, Cairo, Egypt
| | - Anmar M Nassir
- Urology Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abeer A Al Refai
- Faculty of Medicine, Biochemistry Department, Umm Al-Qura University, Makkah, Saudi Arabia.,Faculty of Medicine, Medical Biochemistry and Molecular Biology Department, Menoufia University, Shebin Al-Kom, Egypt
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15
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Analysis of Transcriptome, Selected Intracellular Signaling Pathways, Proliferation and Apoptosis of LNCaP Cells Exposed to High Leptin Concentrations. Int J Mol Sci 2019; 20:ijms20215412. [PMID: 31671654 PMCID: PMC6861914 DOI: 10.3390/ijms20215412] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 10/26/2019] [Accepted: 10/28/2019] [Indexed: 01/03/2023] Open
Abstract
Leptin, the first discovered adipokine, has been connected to various physiological and pathophysiological processes, including cancerogenesis. Increasing evidence confirms its influence on prostate cancer cells. However, studies on the effects of leptin on the proliferation and apoptosis of the androgen-sensitive LNCaP line of prostate cancer cells brought conflicting results. Therefore, we performed studies on the effects of high LEP concentration (1 × 10−6 M) on gene expression profile, change of selected signaling pathways, proliferation and apoptosis of LNCaP cells. RTCA (real-time cell analyzer) revealed inhibitory effect of LEP on cell proliferation, but lower LEP concentrations (10−8 and 10−10 M) did not affect cell division. Moreover, flow cytometry with a specific antibody for Cleaved PARP-1, an apoptosis marker, confirmed the activation of apoptosis in leptin-exposed LNCaP line of prostate cancer cells. Within 24 h LEP (10−6 M) increases expression of 297 genes and decreases expression of 119 genes. Differentially expressed genes (DEGs) were subjected to functional annotation and clusterization using the DAVID bioinformatics tools. Most ontological groups are associated with proliferation and apoptosis (seven groups), immune response (six) and extracellular matrix (two). These results were confirmed by the Gene Set Enrichment Analysis (GSEA). The leptin’s effect on apoptosis stimulation was also confirmed using Pathview library. These results were also confirmed by qPCR method. The results of Western Blot analysis (exposure to LEP 10 min, 1, 2, 4 and 24 h) suggest (after 24 h) decrease of p38 MAPK, p44-42 mitogen-activated protein kinase and Bcl-2 phosphorylated at threonine 56. Moreover, exposure of LNCaP cells to LEP significantly stimulates the secretion of matrix metallopeptidase 7 (MMP7). Obtained results suggest activation of apoptotic processes in LNCaP cells cultured at high LEP concentration. At the same time, this activation is accompanied by inhibition of proliferation of the tested cells.
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16
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The influence of leptin on the process of carcinogenesis. Contemp Oncol (Pozn) 2019; 23:63-68. [PMID: 31316286 PMCID: PMC6630388 DOI: 10.5114/wo.2019.85877] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 04/29/2019] [Indexed: 12/14/2022] Open
Abstract
Obesity is a new risk factor, to which more and more research is devoted, related to the development of cancer. Many studies of recent years have drawn attention to the role of adipose tissue as an important internal endocrine organ. In the adipose tissue proteins are produced, referred to by the common name as adipokines. In the case of obesity, the neoplasm cells are constantly stimulated by pro-inflammatory cytokines and adipokines, among which leptin dominates. The studies show that leptin can affect the cancer cells through numerous phenomena, e.g. inflammation, cell proliferation, suppression of apoptosis and angiogenesis. In this literature review we examined the role of leptin in the development of the individual cancers: breast cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer and brain neoplasms: glioma and meningioma. However, leptin has very complicated mechanisms of action which require better understanding in certain types of cancer.
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17
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Wang YX, Zhu N, Zhang CJ, Wang YK, Wu HT, Li Q, Du K, Liao DF, Qin L. Friend or foe: Multiple roles of adipose tissue in cancer formation and progression. J Cell Physiol 2019; 234:21436-21449. [PMID: 31054175 DOI: 10.1002/jcp.28776] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/15/2019] [Accepted: 04/17/2019] [Indexed: 12/19/2022]
Abstract
Obesity is well-known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity-related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity-related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy.
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Affiliation(s)
- Yu-Xiang Wang
- School of Pharmacy, Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Neng Zhu
- Department of Urology, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Chan-Juan Zhang
- School of Pharmacy, Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Yi-Kai Wang
- Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia
| | - Hong-Tao Wu
- Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qun Li
- Outpatient Department of Hanpu Campus, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Ke Du
- School of Pharmacy, Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Duan-Fang Liao
- Division of Stem Cell Regulation and Application, Key Lab for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Li Qin
- School of Pharmacy, Division of Stem Cell Regulation and Application, Hunan University of Chinese Medicine, Changsha, Hunan, China
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18
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Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling. Neuromolecular Med 2019; 21:192-203. [DOI: 10.1007/s12017-019-08536-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 04/08/2019] [Indexed: 10/27/2022]
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19
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Di Francesco S, Robuffo I, Caruso M, Giambuzzi G, Ferri D, Militello A, Toniato E. Metabolic Alterations, Aggressive Hormone-Naïve Prostate Cancer and Cardiovascular Disease: A Complex Relationship. ACTA ACUST UNITED AC 2019; 55:medicina55030062. [PMID: 30866568 PMCID: PMC6473682 DOI: 10.3390/medicina55030062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/30/2019] [Accepted: 02/27/2019] [Indexed: 02/06/2023]
Abstract
Background: Epidemiological studies suggest a possible relationship between metabolic alterations, cardiovascular disease and aggressive prostate cancer, however, no clear consensus has been reached. Objective: The aim of the study was to analyze the recent literature and summarize our experience on the association between metabolic disorders, aggressive hormone-naïve prostate cancer and cardiovascular disease. Method: We identified relevant papers by searching in electronic databases such as Scopus, Life Science Journals, and Index Medicus/Medline. Moreover, we showed our experience on the reciprocal relationship between metabolic alterations and aggressive prostate cancer, without the influence of hormone therapy, as well the role of coronary and carotid vasculopathy in advanced prostate carcinoma. Results: Prostate cancer cells have an altered metabolic homeostatic control linked to an increased aggressivity and cancer mortality. The absence of discrimination of risk factors as obesity, systemic arterial hypertension, diabetes mellitus, dyslipidemia and inaccurate selection of vascular diseases as coronary and carotid damage at initial diagnosis of prostate cancer could explain the opposite results in the literature. Systemic inflammation and oxidative stress associated with metabolic alterations and cardiovascular disease can also contribute to prostate cancer progression and increased tumor aggressivity. Conclusions: Metabolic alterations and cardiovascular disease influence aggressive and metastatic prostate cancer. Therefore, a careful evaluation of obesity, diabetes mellitus, dyslipidemia, systemic arterial hypertension, together with a careful evaluation of cardiovascular status, in particular coronary and carotid vascular disease, should be carried out after an initial diagnosis of prostatic carcinoma.
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Affiliation(s)
- Simona Di Francesco
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
| | - Iole Robuffo
- Institute of Molecular Genetics, National Research Council, Section of Chieti, 66100 Chieti, Italy.
| | - Marika Caruso
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
| | - Giulia Giambuzzi
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
| | - Deborah Ferri
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
| | - Andrea Militello
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
- Urology and Andrology Section, Villa Immacolata Hospital, 01100 Viterbo, Italy.
| | - Elena Toniato
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
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20
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da Rocha RG, Santos EMS, Santos EM, Gomes ESB, Ramos GV, Aguiar KM, Gonçalves BR, Santos SHS, De Paula AMB, Guimarães ALS, Farias LC. Leptin impairs the therapeutic effect of ionizing radiation in oral squamous cell carcinoma cells. J Oral Pathol Med 2018; 48:17-23. [PMID: 30290014 DOI: 10.1111/jop.12786] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 08/15/2018] [Accepted: 09/30/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE Leptin, an important hormone controlling energy homeostasis, has been linked to the pathogenesis of oral squamous cell carcinoma (OSCC). Evidence indicates that head and neck cancer patients undergoing radiotherapy show decreased leptin levels after radiotherapy treatment. Thus, we investigated, through phenotypic and molecular analyses, whether leptin can compromise the therapeutic effect of ionizing radiation and neoplastic behavior of OSCC cells. METHODS The human OSCC-derived cell lines SCC9 and SCC4 were treated with human recombinant leptin and exposed to 6 Gy of irradiation. We performed the in vitro assays of cell migration, death, proliferation, and colony-forming ability. The reactive oxygen species (ROS) levels and proteome analysis by mass spectrometry were also conducted. RESULTS Leptin was able to increase cell proliferation, migration, and colony-forming ability, despite the suppressive effect induced by irradiation. Furthermore, the leptin promoted a significant reduction of ROS intracellular accumulation, and increased expression of the cancer-related proteins, as ACTC1, KRT6A, and EEF2 in irradiated OSCC cells. CONCLUSIONS Our findings suggest that leptin impairs responsivity of OSCC cells to the ionizing radiation, reducing the suppressive effects of irradiation on the neoplastic phenotype, and increasing protein expression critical to carcinogenesis.
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Affiliation(s)
- Rogério Gonçalves da Rocha
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Eliane Macedo Sobrinho Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.,Instituto Federal do Norte de Minas Gerais - Campus Araçuaí, Montes Claros, Minas Gerais, Brazil
| | - Eloá Mangabeira Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Emisael Stênio Batista Gomes
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Guilherme Veloso Ramos
- Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Karina Marini Aguiar
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | | | - Sérgio Henrique Sousa Santos
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.,Institute of Agricultural Sciences, Food Engineering College, Universidade Federal de Minas Gerais, Montes Claros, Minas Gerais, Brazil
| | - Alfredo Maurício Batista De Paula
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.,Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - André Luiz Sena Guimarães
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.,Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
| | - Lucyana Conceição Farias
- Laboratory of Health Science, Postgraduate Program in Health Sciences, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil.,Department of Dentistry, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, Brazil
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21
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Jiang S, Li T, Yang Z, Hu W, Yang Y. Deciphering the roles of FOXO1 in human neoplasms. Int J Cancer 2018; 143:1560-1568. [PMID: 29473160 DOI: 10.1002/ijc.31338] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 02/10/2018] [Accepted: 02/15/2018] [Indexed: 12/21/2022]
Abstract
Neoplasms constituted an enormous burden and contributed to an estimated 8.2 million deaths in 2012 worldwide. FOXO1 (forkhead box O1), a member of the forkhead box (FOX) family, is a transcriptional factor involved in diverse cellular functions. Herein, we concentrate on recent studies of the antineoplastic roles of FOXO1 in neoplasms. This article may serve as a guide for future research and identify FOXO1 as a potent therapeutic target in neoplasms.
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Affiliation(s)
- Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Tian Li
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Zhi Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Wei Hu
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an, 710069, China
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, China
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22
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Di Sebastiano KM, Pinthus JH, Duivenvoorden WCM, Mourtzakis M. Glucose impairments and insulin resistance in prostate cancer: the role of obesity, nutrition and exercise. Obes Rev 2018; 19:1008-1016. [PMID: 29573216 DOI: 10.1111/obr.12674] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 01/04/2018] [Accepted: 01/15/2018] [Indexed: 01/21/2023]
Abstract
BACKGROUND Hyperinsulinemia, obesity and related metabolic diseases are associated with prostate cancer development. Prostate cancer patients undergoing androgen deprivation therapy (ADT) are at increased risk for metabolic syndrome, cardiovascular disease and diabetes, while pre-existing metabolic conditions may be exacerbated. PURPOSE An integrative approach is used to describe the interactions between insulin, glucose metabolism, obesity and prostate cancer. The potential role of nutrition and exercise will also be examined. FINDINGS Hyperinsulinemia is associated with prostate cancer development, progression and aggressiveness. Prostate cancer patients who undergo ADT are at risk of diabetes in survivorship. It is unclear whether this is a direct result of treatment or related to pre-existing metabolic features (e.g. hyperinsulinemia and obesity). Obesity and metabolic syndrome are also associated with prostate cancer development and poorer outcomes for cancer survivors, which may be driven by hyperinsulinemia, pro-inflammation, hyperleptinemia and/or hypoadiponectinemia. CONCLUSIONS Independently evaluating changes in glucose metabolism near the time of prostate cancer diagnosis and during long-term ADT treatment is important to distinguish their unique contributions to the development of metabolic disturbances. Integrative approaches, including metabolic, clinical and body composition measures, are needed to understand the role of adiposity and insulin resistance in prostate cancer and to develop effective nutrition and exercise interventions to improve secondary diseases in survivorship.
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Affiliation(s)
- K M Di Sebastiano
- Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada
| | - J H Pinthus
- Department of Surgery, Division of Urology, McMaster University, Hamilton, ON, Canada
| | - W C M Duivenvoorden
- Department of Surgery, Division of Urology, McMaster University, Hamilton, ON, Canada
| | - M Mourtzakis
- Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada
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23
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Su L, Qiao Q, Li R, Wu H. Leptin attenuates the growth of rabbit mesenchymal stem cells via the extracellular signal-regulated kinase signaling pathway. Exp Ther Med 2018; 15:4185-4190. [PMID: 29731817 PMCID: PMC5920699 DOI: 10.3892/etm.2018.5948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 01/03/2018] [Indexed: 11/29/2022] Open
Abstract
When stimulated, mesenchymal stem cells (MSCs) may differentiate into chondroblasts, adipocytes or osteoblasts. Leptin is an adipocyte-derived hormone, which regulates food intake and glucose homeostasis. The aim of the present study was to identify the potential role of mitogen-activated protein kinase in the leptin-induced growth of rabbit bone MSCs (rBMSCs). Various concentrations of leptin were used to culture rBMSCs and the viability of cells was observed as well as alterations in the phosphorylation state of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase and p38. It was revealed that the growth of leptin-treated rBMSCs was primarily inhibited by phosphorylated ERK1/2, which was mediated by the leptin receptor. In conclusion, the results of the present study demonstrated that leptin inhibits the growth of rBMSCs principally via the ERK1/2 signaling pathway.
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Affiliation(s)
- Liping Su
- School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P.R. China
| | - Qiao Qiao
- Obstetrics and Gynecology Department, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P.R. China
| | - Ruifeng Li
- Department of Cervical Surgery, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia 010010, P.R. China
| | - Huiguang Wu
- Animal Science College, Inner Mongolia University for The Nationalities, Tongliao, Inner Mongolia 028000, P.R. China
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24
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Hu MB, Xu H, Hu JM, Zhu WH, Yang T, Jiang HW, Ding Q. Genetic polymorphisms in leptin, adiponectin and their receptors affect risk and aggressiveness of prostate cancer: evidence from a meta-analysis and pooled-review. Oncotarget 2018; 7:81049-81061. [PMID: 27768592 PMCID: PMC5348375 DOI: 10.18632/oncotarget.12747] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Accepted: 10/12/2016] [Indexed: 01/04/2023] Open
Abstract
Leptin and adiponectin signaling was associated with development and progression of various cancers. The present study aimed to clarify the role of genetic variants in leptin, adiponectin and their receptors in prostate cancer. After comprehensive search and manuscript scanning, a total of 49 genetic variants were enrolled and examined for their relations to cancer risk and aggressiveness. In the meta-analysis, LEP rs7799039 (allele contrast: OR 1.133, 95%CI 1.024-1.254), ADIPOQ rs2241766 (allele contrast: OR 1.201, 95%CI 1.015-1.422) and ADIPOR1 rs10920531 (allele contrast: OR 1.184, 95%CI 1.075-1.305) variants were identified to be correlated with increased risk of prostate cancer. On the contrary, LEPR rs1137101 (allele contrast: OR 0.843, 95%CI 0.730-0.973) and ADIPOR1 rs2232853 (allele contrast: OR 0.638, 95%CI 0.535-0.760) variants were associated with decreased risk of prostate cancer. From the pooled-review, we additionally recognized eight variants associated with cancer risk and another eight variants associated with cancer aggressiveness, respectively. These observations indicated important roles of leptin, adiponectin and their receptors in the development and progression of prostate cancer. The identified polymorphisms might assist in developing better risk-assessment tools, as well as generating novel targeted therapies, especially for obese cancer patients with impaired leptin and adiponectin signaling.
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Affiliation(s)
- Meng-Bo Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Hua Xu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Ji-Meng Hu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Wen-Hui Zhu
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Tian Yang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Hao-Wen Jiang
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qiang Ding
- Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, China
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Crawley D, Chamberlain F, Garmo H, Rudman S, Zethelius B, Holmberg L, Adolfsson J, Stattin P, Carroll P, Van Hemelrijck M. A systematic review of the literature exploring the interplay between prostate cancer and type two diabetes mellitus. Ecancermedicalscience 2018; 12:802. [PMID: 29456619 PMCID: PMC5813911 DOI: 10.3332/ecancer.2018.802] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Indexed: 11/12/2022] Open
Abstract
Prostate cancer (PCa) and type two diabetes mellitus (T2DM) are both increasing prevalent conditions and often occur concurrently. However, the relationship between the two is more complex than just two prevalent conditions co-existing. This review systematically explores the literature around the interplay between the two conditions. It covers the impact of pre-existing T2DM on PCa incidence, grade and stage, as well as exploring the impact of T2DM on PCa outcomes and mortality and the interaction between T2DM and PCa treatments.
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Affiliation(s)
- Danielle Crawley
- Translational Oncology and Urology Research Group, King's College London, London SE1 9RT, UK
| | - Florence Chamberlain
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK
| | - Hans Garmo
- Translational Oncology and Urology Research Group, King's College London, London SE1 9RT, UK
| | - Sarah Rudman
- Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK
| | - Björn Zethelius
- Department of Public Health and Geriatrics, Uppsala University, Uppsala 751 05, Sweden.,Medical Products Agency, Uppsala 751 03, Sweden
| | - Lars Holmberg
- Translational Oncology and Urology Research Group, King's College London, London SE1 9RT, UK.,Department of Surgical Sciences, Uppsala University, Uppsala 751 05, Sweden
| | - Jan Adolfsson
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm 171 77, Sweden
| | - Par Stattin
- Department of Surgical Sciences, Uppsala University, Uppsala 751 05, Sweden
| | - Paul Carroll
- Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT UK
| | - Mieke Van Hemelrijck
- Translational Oncology and Urology Research Group, King's College London, London SE1 9RT, UK
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26
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Cao Q, Zhu X, Zhai X, Ji L, Cheng F, Zhu Y, Yu P, Zhou Y. Leptin suppresses microRNA-122 promoter activity by phosphorylation of foxO1 in hepatic stellate cell contributing to leptin promotion of mouse liver fibrosis. Toxicol Appl Pharmacol 2018; 339:143-150. [DOI: 10.1016/j.taap.2017.12.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 12/05/2017] [Accepted: 12/13/2017] [Indexed: 01/08/2023]
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27
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Ray A, Cleary MP. The potential role of leptin in tumor invasion and metastasis. Cytokine Growth Factor Rev 2017; 38:80-97. [PMID: 29158066 DOI: 10.1016/j.cytogfr.2017.11.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 11/07/2017] [Indexed: 02/07/2023]
Abstract
The adipocyte-released hormone-like cytokine/adipokine leptin behaves differently in obesity compared to its functions in the normal healthy state. In obese individuals, elevated leptin levels act as a pro-inflammatory adipokine and are associated with certain types of cancers. Further, a growing body of evidence suggests that higher circulating leptin concentrations and/or elevated expression of leptin receptors (Ob-R) in tumors may be poor prognostic factors. Although the underlying pathological mechanisms of leptin's association with poor prognosis are not clear, leptin can impact the tumor microenvironment in several ways. For example, leptin is associated with a number of biological components that could lead to tumor cell invasion and distant metastasis. This includes interactions with carcinoma-associated fibroblasts, tumor promoting effects of infiltrating macrophages, activation of matrix metalloproteinases, transforming growth factor-β signaling, etc. Recent studies also have shown that leptin plays a role in the epithelial-mesenchymal transition, an important phenomenon for cancer cell migration and/or metastasis. Furthermore, leptin's potentiating effects on insulin-like growth factor-I, epidermal growth factor receptor and HER2/neu have been reported. Regarding unfavorable prognosis, leptin has been shown to influence both adenocarcinomas and squamous cell carcinomas. Features of poor prognosis such as tumor invasion, lymph node involvement and distant metastasis have been recorded in several cancer types with higher levels of leptin and/or Ob-R. This review will describe the current scenario in a precise manner. In general, obesity indicates poor prognosis in cancer patients.
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Affiliation(s)
- Amitabha Ray
- Lake Erie College of Osteopathic Medicine, Seton Hill University, Greensburg, PA 15601, United States
| | - Margot P Cleary
- The Hormel Institute, University of Minnesota, Austin, MN 55912, United States.
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Sarmento-Cabral A, L-López F, Luque RM. Adipokines and Their Receptors Are Widely Expressed and Distinctly Regulated by the Metabolic Environment in the Prostate of Male Mice: Direct Role Under Normal and Tumoral Conditions. Endocrinology 2017; 158:3540-3552. [PMID: 28938461 DOI: 10.1210/en.2017-00370] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 08/03/2017] [Indexed: 12/15/2022]
Abstract
Adipose tissue-derived adipokines (i.e., leptin/adiponectin/resistin) play important roles in the regulation of several pathophysiologic processes through the activation of specific receptors. However, although adipokines and their receptors are widely distributed in many tissues and exhibit a clear modulation according to particular metabolic conditions (e.g., obesity and/or fasting), their expression, regulation, and putative action on normal prostate glands (PGs; a hormone-dependent organ tightly regulated by the endocrine-metabolic milieu) are still to be defined. Different in vivo/in vitro models were used to comprehensively characterize the expression pattern and actions of different adipokine systems (i.e., leptin/adiponectin/resistin/receptors) in mouse PGs. Adiponectin, resistin, and adiponectin receptors (1 and 2) and leptin receptor are coexpressed at different levels in PG cells, wherein they are finely regulated under fasting and/or obesity conditions. Furthermore, treatment with different adipokines exerted both homologous and heterologous regulation of specific adipokines/receptor-synthesis and altered the expression of key proliferation and oncogenesis markers (i.e., Ki67/c-Myc/p53) in mouse PG cell cultures, wherein some of these actions might be elicited through extracellular signal-regulated kinase (ERK) activation. Moreover, treatment with leptin, adiponectin, and resistin differentially regulated key functional parameters [i.e., proliferation and migration capacity and/or prostate-specific antigen (PSA) secretion] in human normal and/or tumoral prostate cell lines. Altogether, our data show that various adipokine and receptor systems are differentially expressed in normal PG cells; that their expression is under a complex ligand- and receptor-selective regulation under extreme metabolic conditions; and that they mediate distinctive and common direct actions in normal and tumoral PG cells (i.e., homologous and heterologous regulation of ligand and receptor synthesis, ERK signaling activation, modulation of proliferation markers, proliferation and migration capacity, and PSA secretion), suggesting a relevant role of these systems in the regulation of PG pathophysiology.
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Affiliation(s)
- André Sarmento-Cabral
- Maimonides Institute of Biomedical Research of Cordoba, 14004 Cordoba, Spain
- Reina Sofía University Hospital, 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition, 14004 Cordoba, Spain
- Internacional Campus of Excellence on Agrifood, 14004 Cordoba, Spain
| | - Fernando L-López
- Maimonides Institute of Biomedical Research of Cordoba, 14004 Cordoba, Spain
- Reina Sofía University Hospital, 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition, 14004 Cordoba, Spain
- Internacional Campus of Excellence on Agrifood, 14004 Cordoba, Spain
| | - Raúl M Luque
- Maimonides Institute of Biomedical Research of Cordoba, 14004 Cordoba, Spain
- Reina Sofía University Hospital, 14004 Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
- CIBER Physiopathology of Obesity and Nutrition, 14004 Cordoba, Spain
- Internacional Campus of Excellence on Agrifood, 14004 Cordoba, Spain
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29
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Lee YC, Wu WJ, Lin HH, Li WM, Huang CN, Hsu WC, Chang LL, Li CC, Yeh HC, Li CF, Ke HL. Prognostic Value of Leptin Receptor Overexpression in Upper Tract Urothelial Carcinomas in Taiwan. Clin Genitourin Cancer 2017; 15:e653-e659. [PMID: 28188048 DOI: 10.1016/j.clgc.2017.01.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 12/27/2016] [Accepted: 01/03/2017] [Indexed: 01/11/2023]
Abstract
OBJECTIVES Leptin and its receptor (LEPR) are key players in the regulation of energy balance and body weight control and act as a growth factor for specific organs in both normal and disease states. However, LEPR accumulation may be involved in carcinogenesis, progression, and metastasis in many cancers. This study evaluated the clinical significance of LEPR expression in upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS LEPR expression was examined in 110 tissue samples from patients with UTUC, using immunohistochemistry, and an analysis was performed to identify evidence of association between LEPR expression and different clinicopathologic variables. RESULTS LEPR expression was significantly correlated with patients with increased body mass index (P < .001) and high serum creatinine levels (P = .005). We found, using the log-rank test, that high LEPR expression was associated with poor recurrence-free (P = .009) and cancer-specific survival (P = .001). This finding was supported by our results using Cox regression analysis, which showed that LEPR expression was an independent predictor of poor recurrence-free survival (hazard ratio = 2.55; P = .011) and cancer-specific survival (hazard ratio = 2.26; P = .006). CONCLUSIONS Our findings indicate that LEPR expression is a potential biomarker for predicting patient survival in UTUC. Further study is necessary to investigate the role of LEPR in carcinogenesis of UTUC.
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Affiliation(s)
- Yi-Chen Lee
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Jeng Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Hui-Hui Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Ming Li
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan
| | - Chun-Nung Huang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wei-Chi Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lin-Li Chang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Microbiology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Chia Li
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Hsin-Chih Yeh
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Chien-Feng Li
- Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan; National Cancer Research Institute, National Health Research Institutes, Tainan, Taiwan
| | - Hung-Lung Ke
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Adipocytes promote prostate cancer stem cell self-renewal through amplification of the cholecystokinin autocrine loop. Oncotarget 2016; 7:4939-48. [PMID: 26700819 PMCID: PMC4826255 DOI: 10.18632/oncotarget.6643] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2015] [Accepted: 11/27/2015] [Indexed: 12/18/2022] Open
Abstract
Obesity has long been linked with prostate cancer progression, although the underlying mechanism is still largely unknown. Here, we report that adipocytes promote the enrichment of prostate cancer stem cells (CSCs) through a vicious cycle of autocrine amplification. In the presence of adipocytes, prostate cancer cells actively secrete the peptide hormone cholecystokinin (CCK), which not only stimulates prostate CSC self-renewal, but also induces cathepsin B (CTSB) production of the adipocytes. In return, CTSB facilitates further CCK secretion by the cancer cells. More importantly, inactivation of CCK receptor not only suppresses CTSB secretion by the adipocytes, but also synergizes the inhibitory effect of CTSB inhibitor on adipocyte-promoted prostate CSC self-renewal. In summary, we have uncovered a novel mechanism underlying the mutual interplay between adipocytes and prostate CSCs, which may help explaining the role of adipocytes in prostate cancer progression and provide opportunities for effective intervention.
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31
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Alshaker H, Sacco K, Alfraidi A, Muhammad A, Winkler M, Pchejetski D. Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma. Oncotarget 2016; 6:35556-63. [PMID: 26376613 PMCID: PMC4742124 DOI: 10.18632/oncotarget.5574] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/16/2015] [Indexed: 01/22/2023] Open
Abstract
The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited.Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive.Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.
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Affiliation(s)
- Heba Alshaker
- Department of Surgery and Cancer, Imperial College London, London, UK.,Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, Petra University, Amman, Jordan
| | - Keith Sacco
- University of Malta Medical School, Mater Dei Hospital, Tal-Qroqq, MSD, Malta
| | - Albandri Alfraidi
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Aun Muhammad
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Mathias Winkler
- Department of Surgery and Cancer, Imperial College London, London, UK
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32
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Association of plasma adiponectin and leptin levels with the development and progression of ovarian cancer. Obstet Gynecol Sci 2016; 59:279-85. [PMID: 27462594 PMCID: PMC4958673 DOI: 10.5468/ogs.2016.59.4.279] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 02/11/2016] [Accepted: 02/21/2016] [Indexed: 12/24/2022] Open
Abstract
Objective Decreased adiponectin and increased leptin plasma concentrations are believed to be associated with the occurrence and progression of cancers such as endometrial cancer and breast cancer. The aim of this study was to explore the association of plasma adiponectin and leptin levels with the development and progression of ovarian cancer. Methods For patients with ovarian cancer and the control group, adiponectin and leptin levels were measured; anthropometric data were obtained during a chart review. Statistical comparisons between groups were analyzed using the Student's t-test; correlations were confirmed using the Pearson correlation. Results The mean adiponectin and leptin concentrations in patients with ovarian cancer were lower than those of the control group (8.25 vs. 11.44 µg/mL, respectively; P=0.026) (7.09 vs. 15.4 ng/mL, respectively; P=0.001). However, there was no significant difference in adiponectin and leptin levels between early-stage (I/II) and advanced-stage (III/IV) disease (P=0.078). Conclusion Compared with other gynecological cancers, the level of adiponectin and leptin were decreased in ovarian cancer that may have some diagnostic value; additional study to elucidate the function of these two hormones in the development of ovarian carcinogenesis is necessitated.
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Polvani S, Tarocchi M, Tempesti S, Bencini L, Galli A. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World J Gastroenterol 2016; 22:2441-2459. [PMID: 26937133 PMCID: PMC4768191 DOI: 10.3748/wjg.v22.i8.2441] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/17/2015] [Accepted: 01/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.
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34
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Feng H, Guo P, Wang J, Xu J, Xie C, Gao F. Expression of Leptin and Sirtuin-1 is associated with poor prognosis in patients with osteosarcoma. Pathol Res Pract 2016; 212:319-24. [PMID: 26936024 DOI: 10.1016/j.prp.2016.02.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/29/2015] [Accepted: 02/01/2016] [Indexed: 11/18/2022]
Abstract
Sirtuin-1 (SIRT1) is a downstream target of Leptin, and its inhibition promotes p53-mediated apoptosis. This study aimed to evaluate the expression and prognostic significance of Leptin and SIRT1 in osteosarcoma. Leptin and SIRT1 levels in osteosarcoma samples from 89 patients were evaluated by immunohistochemical staining. The correlations between Leptin and SIRT1 expression with clinical parameters were analyzed by Spearman's test and Pearson's chi-squared test. Prognostic factors were identified by Univariate and multivariate Cox regression analysis. We found that Leptin and SIRT1 expression was low in 23.6% and 20.2%; moderate in 25.8% and 24.7%; and high in 50.5% and 55.1% of patients with osteosarcoma, respectively. Both Leptin and SIRT1 expression were significantly associated with the Enneking stage, distant metastasis and neo-adjuvant chemotherapy. Leptin expression and SIRT1 expression were significantly correlated and they were significantly associated with shorter overall survival. Among osteosarcoma patients who received neo-adjuvant chemotherapy, both Leptin and SIRT1 expression were significantly associated with overall survival of osteosarcoma patients in univariate analysis, but only SIRT1 expression was significantly associated with overall survival of osteosarcoma patients in multivariate analysis. In conclusion, Leptin and SIRT1 expressions are significantly associated with shorter overall survival of osteosarcoma patients, and SIRT1 expression is a significant independent prognostic indicator in patients with osteosarcoma.
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Affiliation(s)
- Helin Feng
- Key Laboratory of Physiology and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 20 Nanerhuan East Road, Shijiazhuang 050024, Hebei, China; Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang 050011, Hebei, China
| | - Peng Guo
- Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang 050011, Hebei, China
| | - Jin Wang
- Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang 050011, Hebei, China
| | - Jianfa Xu
- Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang 050011, Hebei, China
| | - Congcong Xie
- Key Laboratory of Physiology and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 20 Nanerhuan East Road, Shijiazhuang 050024, Hebei, China
| | - Fulu Gao
- Key Laboratory of Physiology and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, 20 Nanerhuan East Road, Shijiazhuang 050024, Hebei, China.
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35
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Serum 17β-estradiol fails as a marker in identification of aggressive tumour disease in patients with localized prostate cancer. World J Urol 2015; 33:1979-84. [DOI: 10.1007/s00345-015-1567-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 04/17/2015] [Indexed: 10/23/2022] Open
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