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Su Y, Mei L, Wu Y, Li C, Jiang T, Zhao Y, Feng X, Sun T, Li Y, Wang Z, Ji Y. Xenotropic and polytropic retrovirus receptor 1 (XPR1) promotes progression of papillary thyroid carcinoma via the BRAF-ERK1/2-P53 signaling pathway. J Endocrinol Invest 2025; 48:633-652. [PMID: 39487939 DOI: 10.1007/s40618-024-02481-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 10/19/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Xenotropic and polytropic retrovirus receptor 1 (XPR1), identified as a cellular receptor, plays roles in many pathophysiological processes. However, the underlying function and molecular mechanisms of XPR1 in PTC remain unclear. Therefore, this study aimed to elucidate the role of XPR1 in the process of PTC and the potential mechanisms. METHODS RNA-sequencing was performed for gene differential expression analysis in PTC patients' tissues. Immunohistochemical assay, real-time PCR, and western blotting assay were used to determine the expression of XPR1, BRAF, and P53 in PTC tissues. The function of XPR1 on the progression of PTC was explored using in vitro and in vivo experiments. The molecular mechanism of XPR1 was investigated using gene silencing, ELISA, immunofluorescence, western blotting, and real-time PCR assays. RESULTS We found that XPR1 was markedly upregulated in PTC tissues compared to adjacent noncancerous tissues, suggesting that high expression of XPR1 could be correlated with poor patient disease-free survival in PTC. In addition, the expression of BRAF and P53 in PTC tissues was substantially higher than in adjacent noncancerous tissues. Silencing of XPR1 reduced the proliferation, migration, and invasion capacities of TPC-1 cells in vitro and effectively inhibited the tumorigenecity of PTC in vivo. More importantly, silencing of XPR1 in TPC-1 cells significantly decreased the expression of XPR1, BRAF, and P53 both in vitro and in vivo. Interestingly, we demonstrated that XPR1 may positively activate the BRAF-ERK-P53 signaling pathway, further promoting PTC progression. CONCLUSION The findings reveal a crucial role of XPR1 in PTC progression and prognosis via the BRAF-ERK1/2-P53 signaling pathway, providing potential therapeutic targets for treating PTC.
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Affiliation(s)
- Yuanhao Su
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Lin Mei
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, Shaanxi, China
| | - Yongke Wu
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Cheng Li
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Tiantian Jiang
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Yiyuan Zhao
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Xin Feng
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Tingkai Sun
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Yunhao Li
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Zhidong Wang
- Department of Geriatric General Surgery, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
| | - Yuanyuan Ji
- Scientific Research Center and Precision Medical Institute, The Second Affiliated Hospital, Xi'an Jiaotong University, 157 West 5th Road, Xi'an, 710004, Shaanxi, China.
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Li S, FeiyuTeng, Zhang J, Zhang P, Li M, Wang X, Li K. Tanshinone IIA potentiates the chemotherapeutic effect of doxorubicin against breast cancer cells and attenuates the cardiotoxicity of doxorubicin by regulating ERK1/2 pathway. J Biochem Mol Toxicol 2024; 38:e23851. [PMID: 39267350 DOI: 10.1002/jbt.23851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/07/2024] [Accepted: 09/03/2024] [Indexed: 09/17/2024]
Abstract
Doxorubicin (Dox) is frequently employed as a chemotherapy agent for breast cancer. As the chemotherapy moves forward, breast cancer cells tend to develop resistance to Dox, besides that, Dox are also easy to cause cardiotoxicity related to cumulative dose. Therefore, how to potentiate the chemosensitivity of breast cancer cells to Dox while attenuating its cardiotoxicity has become a research hotspot. Tanshinone IIA (Tan IIA) is known for its anticancer activity as well as for its cardioprotective effects. In view of the aforementioned facts, we assessed whether Tan IIA possesses synergism and attenuation effect on Dox for breast cancer chemotherapy. Our studies in vitro indicated that, Tan IIA could potentiate the effect of Dox on breast cancer cells proliferation inhibition and apoptosis promotion by inhibiting ERK1/2 pathway, but interestingly, Tan IIA attenuated the cytotoxicity of Dox to myocardial cells by activating ERK1/2 pathway. Additionally, our studies in vivo also suggested that Tan IIA potentiated the chemotherapeutic effect of Dox against breast cancer while attenuating Dox-induced myocardial injury. Given that Tan IIA had a synergism and attenuation effect on Dox, we believed that Tan IIA can be used as an ideal drug in combination with Dox for breast cancer therapy.
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Affiliation(s)
- Shizheng Li
- Department of Emergency Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - FeiyuTeng
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Jianing Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Puwei Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Manyuan Li
- Department of Clinical Laboratory, Jinzhou Women and Children's Hospital, Jinzhou, China
| | - Xuezhe Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
| | - Kun Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, China
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3
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Lacerda-Abreu MA, Meyer-Fernandes JR. Elevated extracellular inorganic phosphate inhibits ecto-phosphatase activity in breast cancer cells: Regulation by hydrogen peroxide. Cell Biol Int 2024; 48:162-173. [PMID: 37818706 DOI: 10.1002/cbin.12095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 09/18/2023] [Accepted: 09/30/2023] [Indexed: 10/12/2023]
Abstract
For cells to obtain inorganic phosphate, ectoenzymes in the plasma membrane, which contain a catalytic site facing the extracellular environment, hydrolyze phosphorylated molecules. In this study, we show that increased Pi levels in the extracellular environment promote a decrease in ecto-phosphatase activity, which is associated with Pi-induced oxidative stress. High levels of Pi inhibit ecto-phosphatase because Pi generates H2 O2 . Ecto-phosphatase activity is inhibited by H2 O2 , and this inhibition is selective for phospho-tyrosine hydrolysis. Additionally, it is shown that the mechanism of inhibition of ecto-phosphatase activity involves lipid peroxidation. In addition, the inhibition of ecto-phosphatase activity by H2 O2 is irreversible. These findings have new implications for understanding ecto-phosphatase regulation in the tumor microenvironment. H2 O2 stimulated by high Pi inhibits ecto-phosphatase activity to prevent excessive accumulation of extracellular Pi, functioning as a regulatory mechanism of Pi variations in the tumor microenvironment.
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Affiliation(s)
- Marco A Lacerda-Abreu
- Instituto de Bioquímica Médica Leopoldo De Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - José R Meyer-Fernandes
- Instituto de Bioquímica Médica Leopoldo De Meis, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
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Bartlett CL, Cave EM, Crowther NJ, Ferris WF. A new perspective on the function of Tissue Non-Specific Alkaline Phosphatase: from bone mineralization to intra-cellular lipid accumulation. Mol Cell Biochem 2022; 477:2093-2106. [PMID: 35471716 DOI: 10.1007/s11010-022-04429-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 03/31/2022] [Indexed: 11/29/2022]
Abstract
Tissue-nonspecific alkaline phosphatase (TNAP) is one of four isozymes, which include germ cell, placental and intestinal alkaline phosphatases. The TNAP isozyme has 3 isoforms (liver, bone and kidney) which differ by tissue expression and glycosylation pattern. Despite a long history of investigation, the exact function of TNAP in many tissues is largely unknown. Only the bone isoform has been well characterised during mineralization where the enzyme hydrolyses pyrophosphate to inorganic phosphate, which combines with calcium to form hydroxyapatite crystals deposited as new bone. The inorganic phosphate also increases gene expression of proteins that support tissue mineralization. Recent studies have shown that TNAP is expressed in preadipocytes from several species, and that inhibition of TNAP activity causes attenuation of intracellular lipid accumulation in these and other lipid-storing cells. The mechanism by which TNAP stimulates lipid accumulation is not known; however, proteins that are important for controlling phosphate levels in bone are also expressed in adipocytes. This review examines the evidence that inorganic phosphate generated by TNAP promotes transcription that enhances the expression of the regulators of lipid storage and consequently, that TNAP has a major function of lipid metabolism.
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Affiliation(s)
- Cara-Lesley Bartlett
- Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa
| | - Eleanor Margaret Cave
- Department of Chemical Pathology, University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa
| | - Nigel John Crowther
- Department of Chemical Pathology, University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa.,Department of Chemical Pathology, National Health Laboratory Service, Johannesburg, South Africa
| | - William Frank Ferris
- Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
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5
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Lacerda-Abreu MA, Russo-Abrahão T, Rocco-Machado N, Cosentino-Gomes D, Dick CF, Carvalho-Kelly LF, Cunha Nascimento MT, Rocha-Vieira TC, Meyer-Fernandes JR. Hydrogen Peroxide Generation as an Underlying Response to High Extracellular Inorganic Phosphate (Pi) in Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms221810096. [PMID: 34576256 PMCID: PMC8468810 DOI: 10.3390/ijms221810096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 11/16/2022] Open
Abstract
According to the growth rate hypothesis (GRH), tumour cells have high inorganic phosphate (Pi) demands due to accelerated proliferation. Compared to healthy individuals, cancer patients present with a nearly 2.5-fold higher Pi serum concentration. In this work, we show that an increasing concentration of Pi had the opposite effect on Pi-transporters only in MDA-MB-231 when compared to other breast cell lines: MCF-7 or MCF10-A (non-tumoural breast cell line). Here, we show for the first time that high extracellular Pi concentration mediates ROS production in TNBC (MDA-MB-231). After a short-time exposure (1 h), Pi hyperpolarizes the mitochondrial membrane, increases mitochondrial ROS generation, impairs oxygen (O2) consumption and increases PKC activity. However, after 24 h Pi-exposure, the source of H2O2 seems to shift from mitochondria to an NADPH oxidase enzyme (NOX), through activation of PKC by H2O2. Exogenous-added H2O2 modulated Pi-transporters the same way as extracellular high Pi, which could be reversed by the addition of the antioxidant N-acetylcysteine (NAC). NAC was also able to abolish Pi-induced Epithelial-mesenchymal transition (EMT), migration and adhesion of MDA-MB-231. We believe that Pi transporters support part of the energy required for the metastatic processes stimulated by Pi and trigger Pi-induced H2O2 production as a signalling response to promote cell migration and adhesion.
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Affiliation(s)
- Marco Antonio Lacerda-Abreu
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
| | - Thais Russo-Abrahão
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
| | - Nathália Rocco-Machado
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
- National Heart, Lung, and Blood Institute, NIH, Bethesda, Rockville, MD 20814, USA
| | - Daniela Cosentino-Gomes
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
- Departamento de Bioquímica, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, RJ, Brazil
| | - Claudia Fernanda Dick
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil
| | - Luiz Fernando Carvalho-Kelly
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
| | - Michelle Tanny Cunha Nascimento
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
| | - Thaís Cristino Rocha-Vieira
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
| | - José Roberto Meyer-Fernandes
- Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, RJ, Brazil; (M.A.L.-A.); (T.R.-A.); (N.R.-M.); (D.C.-G.); (C.F.D.); (L.F.C.-K.); (M.T.C.N.); (T.C.R.-V.)
- Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagem, Rio de Janeiro 21941-590, RJ, Brazil
- Correspondence: ; Tel.: +55-21-3938-6781; Fax: +55-21-2270-8647
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6
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Phosphate imbalance conducting by BPs-based cancer-targeting phosphate anions carrier induces necrosis. CHINESE CHEM LETT 2021. [DOI: 10.1016/j.cclet.2020.09.052] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Wu SH, Hsieh CC, Hsu SC, Yao M, Hsiao JK, Wang SW, Lin CP, Huang DM. RBC-derived vesicles as a systemic delivery system of doxorubicin for lysosomal-mitochondrial axis-improved cancer therapy. J Adv Res 2020; 30:185-196. [PMID: 34026295 PMCID: PMC8132207 DOI: 10.1016/j.jare.2020.11.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 11/19/2020] [Accepted: 11/22/2020] [Indexed: 01/07/2023] Open
Abstract
Introduction Chemotherapeutic drugs are the main intervention for cancer management, but many drawbacks impede their clinical applications. Nanoparticles as drug delivery systems (DDSs) offer much promise to solve these limitations. Objectives A novel nanocarrier composed of red blood cell (RBC)-derived vesicles (RDVs) surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs was investigated for improved cancer therapy. Methods We investigated the in vivo antineoplastic performance of Dox-gluRDVs through intravenous (i.v.) administration in the mouse model bearing subcutaneous (s.c.) B16F10 tumor and examined the in vitro antitumor mechanism and efficacy in a panel of cancer cell lines. Results Dox-gluRDVs can exert superior anticancer activity than free Dox in vitro and in vivo. Distinct from free Dox that is mainly located in the nucleus, but instead Dox-gluRDVs release and efficiently deliver the majority of their conjugated Dox into lysosomes. In vitro mechanism study reveals the critical role of lysosomal Dox accumulation-mediated mitochondrial ROS overproduction followed by the mitochondrial membrane potential loss and the activation of apoptotic signaling for superior anticancer activity of Dox-gluRDVs. Conclusion This work demonstrates the great potential of RDVs to serve a biological DDS of Dox for systemic administration to improve conventional cancer chemotherapeutics.
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Affiliation(s)
- Shu-Hui Wu
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Chia-Chu Hsieh
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 35053, Taiwan
| | - Szu-Chun Hsu
- Department of Laboratory Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan
| | - Ming Yao
- Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan
| | - Jong-Kai Hsiao
- Department of Medical Imaging, Taipei Tzu Chi General Hospital, Buddhist Tzu-Chi Medical Foundation, New Taipei City 23142, Taiwan.,School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City 252005, Taiwan
| | - Chih-Peng Lin
- Department of Anesthesiology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100225, Taiwan
| | - Dong-Ming Huang
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli 35053, Taiwan
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8
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Arnst JL, Beck GR. Modulating phosphate consumption, a novel therapeutic approach for the control of cancer cell proliferation and tumorigenesis. Biochem Pharmacol 2020; 183:114305. [PMID: 33129806 DOI: 10.1016/j.bcp.2020.114305] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 01/30/2023]
Abstract
Phosphorus, often in the form of inorganic phosphate (Pi), is critical to cellular function on many levels; it is required as an integral component of kinase signaling, in the formation and function of DNA and lipids, and energy metabolism in the form of ATP. Accordingly, crucial aspects of cell mitosis - such as DNA synthesis and ATP energy generation - elevate the cellular requirement for Pi, with rapidly dividing cells consuming increased levels. Mechanisms to sense, respond, acquire, accumulate, and potentially seek Pi have evolved to support highly proliferative cellular states such as injury and malignant transformation. As such, manipulating Pi availability to target rapidly dividing cells presents a novel strategy to reduce or prevent unrestrained cell growth. Currently, limited knowledge exists regarding how modulating Pi consumption by pre-cancerous cells might influence the initiation of aberrant growth during malignant transformation, and if reducing the bioavailability or suppressing Pi consumption by malignant cells could alter tumorigenesis. The concept of targeting Pi-regulated pathways and/or consumption by pre-cancerous or tumor cells represents a novel approach to cancer prevention and control, although current data remains insufficient as to rigorously assess the therapeutic value and physiological relevance of this strategy. With this review, we present a critical evaluation of the paradox of how an element critical to essential cellular functions can, when available in excess, influence and promote a cancer phenotype. Further, we conjecture how Pi manipulation could be utilized as a therapeutic intervention, either systemically or at the cell level, to ultimately suppress or treat cancer initiation and/or progression.
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Affiliation(s)
- Jamie L Arnst
- Emory University, Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Atlanta, GA 30322, United States
| | - George R Beck
- The Atlanta Department of Veterans Affairs Medical Center, Decatur, GA 30033, United States; Emory University, Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Atlanta, GA 30322, United States; The Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, United States.
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9
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Johari B, Rahmati M, Nasehi L, Mortazavi Y, Faghfoori MH, Rezaeejam H. Evaluation of STAT3 decoy oligodeoxynucleotides' synergistic effects on radiation and/or chemotherapy in metastatic breast cancer cell line. Cell Biol Int 2020; 44:2499-2511. [PMID: 32841450 DOI: 10.1002/cbin.11456] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/30/2020] [Accepted: 08/23/2020] [Indexed: 12/15/2022]
Abstract
Resistance to radiotherapy and chemotherapy has been a major problem of conventional cancer therapies, which consequently leads to cancer relapse and cancer-related death. It is known that cancer stem cells (CSCs) play a key role in therapy resistance and CSC-based targeted therapies have been considered as a powerful tool for cancer treatment. In the current study, we investigated the synergistic effects of suppressing signal transducer and activator of transcription (STAT3) function by decoy ODNs on X-irradiation (XI) and methotrexate (MTX) exposure as a combinational therapy in triple-negative breast cancer (TNBC) MDA-MB-231 cells. Lipofectamine 2000® was used as a transfecting agent and the cells treated with Scramble ODNs (SCR) and decoy ODNs were subjected to irradiation with 2 Gy at single/fractionated (XI group) doses, different concentration of MTX group, and X-irradiation-methotrexate (XI/MTX group). Synergistic effects of STAT3 SCR and decoy ODNs on cells were investigated by cell viability (MTT), cell cycle profile, apoptosis rate, migration, and invasion assays. Statistical analysis of obtained data showed that STAT3 decoy ODNs significantly decreased the cell viability, arrested the growth at G0/G1 phase, increased apoptosis rate, and reduced migrated and invaded cells through transwell membrane, in XI, MTX, and XI/MTX exposed groups. Since STAT3 is a master transcription factor in breast cancer cells stemness, aggressiveness, TNBC's heterogeneity, and therapy resistance; therefore, inhibition of this transcription factor by decoy ODNs could increase antitumor efficiencies of XI and MTX exposure strategies. Accordingly, this method could have the potential to increase the efficiency of combination therapies.
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Affiliation(s)
- Behrooz Johari
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.,Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohammad Rahmati
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Leila Nasehi
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.,Department of Medical Laboratory, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Yousef Mortazavi
- Department of Medical Biotechnology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.,Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Hamed Rezaeejam
- Student Research Committee, Zanjan University of Medical Sciences, Zanjan, Iran.,Department of Radiation Oncology, Vali-e-Asr Hospital, Zanjan University of Medical Sciences, Zanjan, Iran.,Department of Radiology, School of Paramedical Sciences, Zanjan University of Medical Sciences, Zanjan, Iran
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10
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Chen D, Ma Y, Li P, Liu M, Fang Y, Zhang J, Zhang B, Hui Y, Yin Y. Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer. Molecules 2019; 24:E2338. [PMID: 31242627 PMCID: PMC6631638 DOI: 10.3390/molecules24122338] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/20/2019] [Accepted: 06/24/2019] [Indexed: 12/18/2022] Open
Abstract
Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.
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Affiliation(s)
- Di Chen
- Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Technology, Xi'an 710021, China.
- School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China.
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
| | - Yangmin Ma
- Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Peiqi Li
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
| | - Meng Liu
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
| | - Yuan Fang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
| | - Jiejie Zhang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
| | - Bilin Zhang
- Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an 710021, China.
| | - Yuyu Hui
- Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of Science and Technology, Xi'an 710021, China.
| | - Yue Yin
- School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
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11
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Chen WC, Li QL, Pan Q, Zhang HY, Fu XY, Yao F, Wang JN, Yang AK. Xenotropic and polytropic retrovirus receptor 1 (XPR1) promotes progression of tongue squamous cell carcinoma (TSCC) via activation of NF-κB signaling. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:167. [PMID: 30995931 PMCID: PMC6469095 DOI: 10.1186/s13046-019-1155-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 03/27/2019] [Indexed: 01/15/2023]
Abstract
Background Xenotropic and polytropic retrovirus receptor 1 (XPR1), a previously identified cellular receptor for several murine leukemia viruses, plays a role in many pathophysiological processes. However, the role of XPR1 in human cancers has not yet been characterized. Methods Real-time PCR and western blotting assay were used to measure the expression of XPR1 in tongue squamous cell carcinoma (TSCC) tissues. Expression of XPR1 and p65 in clinical specimens was analyzed using immunohistochemical assay. The function of XPR1 on progression of TSCC was explored using in vitro and in vivo experiments. The molecular mechanism by which XPR1 helps to cancer progression was investigated by luciferase reporter activity, ELISA, PKA activity assay, immunofluorescence, western blotting and qPCR assay. Results Herein, we find that XPR1 is markedly upregulated in TSCC tissues compared to normal tongue tissues. High expression of XPR1 significantly correlates with the malignant features and poor patient survival in TSCC. Ectopic expression of XPR1 increases, while silencing of XPR1 reduces the proliferation, invasion and anti-apoptosis capacities of TSCC cells. Importantly, silencing of XPR1 effectively inhibits the tumorigenecity of TSCC cells. Moreover, we identified that XPR1 increased the concentration of intracellular cAMP and activated PKA. Thus, XPR1 promoted phosphorylation and activation of NF-κB signaling, which is required for XPR1-mediated oncogenic roles and significantly correlates with XPR1 expression in clinical specimens. Conclusions These findings uncover a critical role of XPR1 in TSCC progression via activation of NF-κB, and suggest that XPR1 might be a potential prognostic marker or therapeutic target. Electronic supplementary material The online version of this article (10.1186/s13046-019-1155-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei-Chao Chen
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Qiu-Li Li
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Qimei Pan
- Guangzhou Yousheng Biotech Co., Ltd., Guangzhou, Guangdong, 510060, People's Republic of China
| | - Hua-Yong Zhang
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Xiao-Yan Fu
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Fan Yao
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China.,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China.,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China
| | - Jian-Ning Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, Guangdong Province, 510055, People's Republic of China.
| | - An-Kui Yang
- Department of Head and Neck, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, People's Republic of China. .,State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510060, People's Republic of China. .,Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.
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12
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Catauro M, Tranquillo E, Salzillo A, Capasso L, Illiano M, Sapio L, Naviglio S. Silica/Polyethylene Glycol Hybrid Materials Prepared by a Sol-Gel Method and Containing Chlorogenic Acid. Molecules 2018; 23:2447. [PMID: 30257424 PMCID: PMC6222366 DOI: 10.3390/molecules23102447] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/19/2018] [Accepted: 09/21/2018] [Indexed: 12/13/2022] Open
Abstract
Chlorogenic acid (CGA) is a very common dietary polyphenolic compound. CGA is becoming very attractive due to its potential use as preventive and therapeutic agent in many diseases, including cancer. Inorganic/organic hybrid materials are gaining considerable attention in the biomedical field. The sol-gel process provides a useful way to obtain functional organic/inorganic hybrids. The aim of this study was to synthesize silica/polyethylene glycol (PEG) hybrids with different percentages of CGA by sol-gel technique and to investigate their impact on the cancer cell proliferation. Synthesized materials have been chemically characterized through the FTIR spectroscopy and their bioactivity evaluated looking by SEM at their ability to produce a hydroxyapatite layer on their surface upon incubation with simulated body fluid (SBF). Finally, their effects on cell proliferation were studied in cell lines by direct cell number counting, MTT, flow cytometry-based cell-cycle and cell death assays, and immunoblotting experiments. Notably, we found that SiO₂/PEG/CGA hybrids exhibit clear antiproliferative effects in different tumor, including breast cancer and osteosarcoma, cell lines in a CGA dependent manner, but not in normal cells. Overall, our results increase the evidence of CGA as a possible anticancer agent and illustrate the potential for clinical applications of sol-gel synthesized SiO₂/PEG/CGA materials.
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Affiliation(s)
- Michelina Catauro
- Department of Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, I-81031 Aversa, Italy.
| | - Elisabetta Tranquillo
- Department of Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, I-81031 Aversa, Italy.
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Alessia Salzillo
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Lucia Capasso
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Michela Illiano
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Luigi Sapio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Silvio Naviglio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli" Via L. De Crecchio 7, 80138 Naples, Italy.
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13
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Cabrera-Afonso MJ, Lucena SR, Juarranz Á, Urbano A, Carreño MC. Selective Oxidative Dearomatization of Angular Tetracyclic Phenols by Controlled Irradiation under Air: Synthesis of an Angucyclinone-Type Double Peroxide with Anticancer Properties. Org Lett 2018; 20:6094-6098. [DOI: 10.1021/acs.orglett.8b02515] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- María J. Cabrera-Afonso
- Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049-Madrid, Spain
| | | | | | - Antonio Urbano
- Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049-Madrid, Spain
- Institute for Advanced Research in Chemical Sciences (IAdChem), UAM, Cantoblanco, 28049-Madrid, Spain
| | - M. Carmen Carreño
- Departamento de Química Orgánica, Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049-Madrid, Spain
- Institute for Advanced Research in Chemical Sciences (IAdChem), UAM, Cantoblanco, 28049-Madrid, Spain
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14
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Zheng Y, Dai Y, Liu W, Wang N, Cai Y, Wang S, Zhang F, Liu P, Chen Q, Wang Z. Astragaloside IV enhances taxol chemosensitivity of breast cancer via caveolin-1-targeting oxidant damage. J Cell Physiol 2018; 234:4277-4290. [PMID: 30146689 DOI: 10.1002/jcp.27196] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 07/17/2018] [Indexed: 01/09/2023]
Abstract
Accumulating evidence suggests that caveolin-1 (CAV-1) is a stress-related oncotarget and closely correlated to chemoresistance. Targeting CAV-1 might be a promising strategy to improve chemosensitivity for breast cancer treatment. Astragaloside IV (AS-IV), a bioactive compound purified from Astragalus membranaceus, has been shown to exhibit multiple bioactivities, including anticancer. However, the involved molecular targets are still ambiguous. In this study, we investigated the critical role of CAV-1 in mediating the chemosensitizing effects of AS-IV to Taxol on breast cancer. We found that AS-IV could enhance the chemosensitivity of Taxol with minimal direct cytotoxicity on breast cancer cell lines MCF-7 and MDA-MB-231, as well as the nontumor mammary epithelial cell line MCF-10A. AS-IV was further demonstrated to aggravate Taxol-induced apoptosis and G2/M checkpoint arrest. The phosphorylation of mitogen-activated protein kinase (MAPK) signaling extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK), except p38, was also abrogated by a synergistic interaction between AS-IV and Taxol. Moreover, AS-IV inhibited CAV-1 expression in a dose-dependent manner and reversed CAV-1 upregulation induced by Taxol administration. Mechanism study further demonstrated that AS-IV treatment triggered the eNOS/NO/ONOO- pathway via inhibiting CAV-1, which led to intense oxidant damage. CAV-1 overexpression abolished the chemosensitizing effects of AS-IV to Taxol by inhibiting oxidative stress. In vivo experiments further validated that AS-IV increased Taxol chemosensitivity on breast cancer via inhibiting CAV-1 expression, followed by activation of the eNOS/NO/ONOO- pathway. Taken together, our findings not only suggested the potential of AS-IV as a promising candidate to enhance chemosensitivity, but also highlighted the significance of CAV-1 as the target to reverse cancer drug resistance.
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Affiliation(s)
- Yifeng Zheng
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan Dai
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Weiping Liu
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Neng Wang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Youli Cai
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shengqi Wang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Fengxue Zhang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Pengxi Liu
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qianjun Chen
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Zhiyu Wang
- Guangzhou University of Chinese Medicine, Integrative Research Laboratory of Breast Cancer, The Research Centre of Integrative Medicine, Discipline of Integrated Chinese and Western Medicine & The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.,Translational Research Laboratory of Chinese Medicine & Cancer Stress Signaling, College of Basic Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.,Discipline of Integrated Chinese and Western Medicine, Post-Doctoral Research Center, Guangzhou University of Chinese Medicine, Guangzhou, China
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15
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Illiano M, Sapio L, Salzillo A, Capasso L, Caiafa I, Chiosi E, Spina A, Naviglio S. Forskolin improves sensitivity to doxorubicin of triple negative breast cancer cells via Protein Kinase A-mediated ERK1/2 inhibition. Biochem Pharmacol 2018; 152:104-113. [PMID: 29574069 DOI: 10.1016/j.bcp.2018.03.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 03/20/2018] [Indexed: 01/07/2023]
Abstract
Triple negative breast cancer (TNBC) is an invasive, metastatic, highly aggressive tumor. Cytotoxic chemotherapy represents the current treatment for TNBC. However, relapse and chemo-resistance are very frequent. Therefore, new therapeutic approaches that are able to increase the sensitivity to cytotoxic drugs are needed. Forskolin, a natural cAMP elevating agent, has been used for several centuries in medicine and its safeness has also been demonstrated in modern studies. Recently, forskolin is emerging as a possible novel molecule for cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of MDA-MB-231 and MDA-MB-468 TNBC cells to doxorubicin through MTT assay, flow cytometry-based assays (cell-cycle progression and cell death), cell number counting and immunoblotting experiments. We demonstrate that forskolin strongly enhances doxorubicin-induced antiproliferative effects by cell death induction. Similar effects are observed with IBMX and isoproterenol cAMP elevating agents and 8-Br-cAMP analog, but not by using 8-pCPT-2'-O-Me-cAMP Epac activator. It is important to note that the forskolin-induced potentiation of sensitivity to doxorubicin is accompanied by a strong inhibition of ERK1/2 phosphorylation, is mimicked by ERK inhibitor PD98059 and is prevented by pre-treatment with Protein Kinase A (PKA) and adenylate cyclase inhibitors. Altogether, our data indicate that forskolin sensitizes TNBC cells to doxorubicin via a mechanism depending on the cAMP/PKA-mediated ERK inhibition. Our findings sustain the evidence of anticancer activity mediated by forskolin and encourage the design of future in-vivo/clinical studies in order to explore forskolin as a doxorubicin sensitizer for possible use in TNBC patients.
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Affiliation(s)
- Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Alessia Salzillo
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Lucia Capasso
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Ilaria Caiafa
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Emilio Chiosi
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Annamaria Spina
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania "Luigi Vanvitelli", Medical School, Via L. De Crecchio 7, 80138 Naples, Italy.
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16
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Catauro M, Bollino F, Tranquillo E, Sapio L, Illiano M, Caiafa I, Naviglio S. Chemical analysis and anti-proliferative activity of Campania Thymus Vulgaris essential oil. JOURNAL OF ESSENTIAL OIL RESEARCH 2017; 29:461-470. [DOI: 10.1080/10412905.2017.1351405] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Michelina Catauro
- Department of Industrial and Information Engineering, Second University of Naples, Aversa, Italy
| | - Flavia Bollino
- Department of Industrial and Information Engineering, Second University of Naples, Aversa, Italy
| | - Elisabetta Tranquillo
- Department of Industrial and Information Engineering, Second University of Naples, Aversa, Italy
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, Naples, Italy
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, Naples, Italy
| | - Ilaria Caiafa
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, Naples, Italy
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Medical School, Naples, Italy
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17
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Cappetta D, De Angelis A, Sapio L, Prezioso L, Illiano M, Quaini F, Rossi F, Berrino L, Naviglio S, Urbanek K. Oxidative Stress and Cellular Response to Doxorubicin: A Common Factor in the Complex Milieu of Anthracycline Cardiotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:1521020. [PMID: 29181122 PMCID: PMC5664340 DOI: 10.1155/2017/1521020] [Citation(s) in RCA: 252] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 09/18/2017] [Indexed: 12/11/2022]
Abstract
The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.
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Affiliation(s)
- Donato Cappetta
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Antonella De Angelis
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Lucia Prezioso
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Federico Quaini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Francesco Rossi
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Liberato Berrino
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Konrad Urbanek
- Department of Experimental Medicine, Section of Pharmacology, University of Campania Luigi Vanvitelli, Naples, Italy
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18
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Catauro M, Tranquillo E, Illiano M, Sapio L, Spina A, Naviglio S. The Influence of the Polymer Amount on the Biological Properties of PCL/ZrO₂ Hybrid Materials Synthesized via Sol-Gel Technique. MATERIALS (BASEL, SWITZERLAND) 2017; 10:1186. [PMID: 29039803 PMCID: PMC5666992 DOI: 10.3390/ma10101186] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 10/10/2017] [Accepted: 10/13/2017] [Indexed: 12/11/2022]
Abstract
Organic/inorganic hybrid materials are attracting considerable attention in the biomedical area. The sol-gel process provides a convenient way to produce many bioactive organic-inorganic hybrids. Among those, poly(e-caprolactone)/zirconia (PCL/ZrO₂) hybrids have proved to be bioactive with no toxic materials. The aim of this study was to investigate the effects of these materials on the cellular response as a function of the PCL content, in order to evaluate their potential use in the biomedical field. For this purpose, PCL/ZrO₂ hybrids containing 6, 12, 24, and 50 wt % of PCL were synthesized by the sol-gel method. The effects of their presence on the NIH-3T3 fibroblast cell line carrying out direct cell number counting, MTT, cell damage assays, flow cytometry-based analysis of cell-cycle progression, and immunoblotting experiments. The results confirm and extend the findings that PCL/ZrO₂ hybrids are free from toxicity. The hybrids containing 12 and 24 wt % PCL, (more than 6 and 50 wt % ones) enhance cell proliferation when compared to pure ZrO₂ by affecting cell cycle progression. The finding that the content of PCL in PCL/ZrO₂ hybrids differently supports cell proliferation suggests that PCL/ZrO₂ hybrids could be useful tools with different potential clinical applications.
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Affiliation(s)
- Michelina Catauro
- Department of Industrial and Information Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, 81031 Aversa, Italy.
| | - Elisabetta Tranquillo
- Department of Industrial and Information Engineering, University of Campania "Luigi Vanvitelli", Via Roma 29, 81031 Aversa, Italy.
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Michela Illiano
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Luigi Sapio
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Annamaria Spina
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
| | - Silvio Naviglio
- Department of Biochemistry, Biophysics and General Pathology, Medical School, University of Campania "Luigi Vanvitelli", Via L. De Crecchio 7, 80138 Naples, Italy.
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19
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Yang J, Wu Y, Wang X, Xu L, Zhao X, Yang Y. Chemoresistance is associated with overexpression of HAX-1, inhibition of which resensitizes drug-resistant breast cancer cells to chemotherapy. Tumour Biol 2017; 39:1010428317692228. [PMID: 28347249 DOI: 10.1177/1010428317692228] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acquired resistance to standard chemotherapy is the common and critical limitation for cancer therapy. Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) has been reported to be upregulated in numerous cancers. However, the role of HAX-1 in oncotherapy remains unclear. In this study, we established MDA-MB-231 cell lines which were resistant to cisplatin (MDA-MB-231/CR) or doxorubicin (MDA-MB-231/DR) to study the chemoresistance in breast cancer. As a result, the HAX-1 which is an apoptosis-associated protein was observed to be overexpressed in both MDA-MB-231/CR and MDA-MB-231/DR compared with the routine MDA-MB-231 cells. Moreover, knockdown of HAX-1 via RNA interference decreased IC50 level of cisplatin by 70.91% in MDA-MB-231/CR cells, and the IC50 level of doxorubicin was decreased by 76.46% in MDA-MB-231/DR cells when the HAX-1 was downregulated. Additionally, we found that the knockdown of HAX-1 induced the release of cytochrome C from mitochondria, resulting in the activation of caspases. Taken together, our study indicates that the overexpression of HAX-1 is essential in the development of chemoresistance in breast cancer. Furthermore, we identify that HAX-1 may become the target for cancer therapy.
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Affiliation(s)
- Ji Yang
- 1 Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yue Wu
- 1 Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao Wang
- 2 Oncology Department, Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Liqian Xu
- 1 Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaohong Zhao
- 1 Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yunmei Yang
- 1 Department of Geriatrics, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Illiano M, Sapio L, Caiafa I, Chiosi E, Spina A, Naviglio S. Forskolin sensitizes pancreatic cancer cells to gemcitabine via Stat3 and Erk1/2 inhibition. AIMS MOLECULAR SCIENCE 2017. [DOI: 10.3934/molsci.2017.2.224] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Enhanced cytotoxic activity of doxorubicin through the inhibition of autophagy in triple negative breast cancer cell line. Biochim Biophys Acta Gen Subj 2016; 1861:49-57. [PMID: 27842219 DOI: 10.1016/j.bbagen.2016.11.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/01/2016] [Accepted: 11/10/2016] [Indexed: 01/24/2023]
Abstract
BACKGROUND The outcome of triple negative breast cancer is still poor and requires improvement with better therapy options. Autophagy has recently been shown to play a role in anticancer drug resistance. Therefore, we investigated if the effectiveness of doxorubicin was augmented by the inhibition of autophagy. METHODS MDA-MB-231 was used as a model cell line for triple negative breast cancer and 3-methyladenine was used as an inhibitor of autophagy. Cells were treated with 0.46-1.84μM doxorubicin and 2.5-10μM 3-methyladenine for 48h. Cell death mode was examined with M30 and M65 ELISA assays. ROS level and LDH activity was examined and the cellular acidic compartment of cells was monitored by acridine orange staining. The expression of various autophagy and apoptosis related proteins/genes were evaluated with Western blotting and RT-qPCR respectively. RESULTS Synergism was observed between the compounds (CI value<1.0). RT-qPCR analysis revealed that the combination resulted in a down-regulation of autophagy-related genes. Moreover, the combination resulted in a different cell death modality, upregulating necroptosis-related genes. This suggests that the mode of cell death may switch from apoptosis to necroptosis, which is a more severe form of cell death, when autophagy is inhibited. These results were further confirmed at protein level by Western blotting. CONCLUSION Inhibition of autophagy seems to sensitize triple negative breast cancer cells to doxorubicin, warranting further in vivo studies for the proof of this concept. GENERAL SIGNIFICANCE Autophagy has a key role in drug resistance in MDA-MB-231 cells. Therefore combinatorial approaches may effectively overcome resistance.
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Shikonin Inhibits the Proliferation of Human Breast Cancer Cells by Reducing Tumor-Derived Exosomes. Molecules 2016; 21:molecules21060777. [PMID: 27322220 PMCID: PMC6274101 DOI: 10.3390/molecules21060777] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 06/02/2016] [Accepted: 06/07/2016] [Indexed: 01/08/2023] Open
Abstract
Shikonin is a naphthoquinone isolated from the traditional Chinese medicine Lithospermum. It has been used in the treatment of various tumors. However, the effects of shikonin on such diseases have not been fully elucidated. In the present study, we detected the exosome release of a breast cancer cell line (MCF-7) with shikonin treatment and found a positive relationship between the level of secreted exosomes and cell proliferation. We next analyzed miRNA profiles in MCF-7 cells and exosomes and found that some miRNAs are specifically sorted and abundant in exosomes. Knockdown of the most abundant miRNAs in exosomes and the MCF-7 proliferation assay showed that miR-128 in exosomes negatively regulates the level of Bax in MCF-7 recipient cells and inhibits cell proliferation. These results show that shikonin inhibits the proliferation of MCF-7 cells through reducing tumor-derived exosomal miR-128. The current study suggests that shikonin suppresses MCF-7 growth by the inhibition of exosome release.
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Sapio L, Naviglio S. Inorganic phosphate in the development and treatment of cancer: A Janus Bifrons? World J Clin Oncol 2015; 6:198-201. [PMID: 26677430 PMCID: PMC4675902 DOI: 10.5306/wjco.v6.i6.198] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/06/2015] [Accepted: 09/29/2015] [Indexed: 02/06/2023] Open
Abstract
Inorganic phosphate (Pi) is an essential nutrient to living organisms. It is required as a component of the energy metabolism, kinase/phosphatase signaling and in the formation and function of lipids, carbohydrates and nucleic acids and, at systemic level, it plays a key role for normal skeletal and dentin mineralization. Pi represents an abundant dietary element and its intestinal absorption is efficient, minimally regulated and typically extends to approximately 70%. Maintenance of proper Pi homeostasis is a critical event and serum Pi level is maintained within a narrow range through an elaborate network of humoral interactions and feedback loops involving intestine, kidney, parathyroid gland and bone, and depends on the activity of a number of hormones, including parathyroid hormone, 1,25-dihydroxy vitamin D, and fibroblast growth factor 23 as major regulators of Pi homeostasis. Notably, Pi intake seemingly continues to increase as a consequence of chronic high-phosphorus (P) diets deriving from the growing consumption of highly processed foods, especially restaurant meals, fast foods, and convenience foods. Several recent reports have generated significant associations between high-P intake or high-serum Pi concentration and morbidity and mortality. Many chronic diseases, including cardiovascular diseases, obesity and even cancer have been proposed to be associated with high-P intakes and high-serum Pi concentrations. On the other hand, there is also evidence that Pi can have antiproliferative effects on some cancer cell types, depending on cell status and genetic background and achieve additive cytotoxic effects when combined with doxorubicin, illustrating its potential for clinical applications and suggesting that up-regulating Pi levels at local sites for brief times, might contribute to the development of novel and cheap modalities for therapeutic intervention in some tumours. Overall, the influence of Pi on cell function and the possible relationship to cancer have to be fully understood and investigated further.
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miR-27a regulates the sensitivity of breast cancer cells to cisplatin treatment via BAK-SMAC/DIABLO-XIAP axis. Tumour Biol 2015; 37:6837-45. [PMID: 26662313 DOI: 10.1007/s13277-015-4500-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 11/24/2015] [Indexed: 12/14/2022] Open
Abstract
MicroRNA-27a (miR-27a) has been reported to be an onco-microRNA in multiple cancers promoting tumor growth and metastasis, but the role of miR-27a in regulating the cancer sensitivity to chemotherapy remains unknown. In this study, upregulation of miR-27a was validated by real-time PCR analysis in breast cancer (BC) cell lines and samples of BC patients. A negative correlation between miR-27a and bak was also observed in normal breast epithelial cell line MCF-10A and BC cell lines, suggesting that the bak is the potential target of miR-27a. miR-27a could modulate the growth and metastasis of BC cells. More importantly, we found that knockdown of miR-27a by the specific inhibitors significantly increased the sensitivity of T-47D cells to cisplatin (CDDP) treatment. After further investigation, we indicated that the knockdown of miR-27a promoted the apoptosis via mitochondrial pathway in T-47D cells treated with CDDP, depending on the BAK-second mitochondria-derived activator of caspase/direct IAP binding protein with low pI (SMAC/DIABLO)-X-linked inhibitor of apoptosis (XIAP) axis. Interestingly, we found that the sensitivity of T-47D cells to some other chemotherapeutic agents (5-fluorouracil, doxorubicin, and tumor necrosis factor-related apoptosis-inducing ligand) was also regulated by miR-27a. These findings improve our understanding of the role of miR-27a in breast cancer and might provide a novel strategy for cancer therapy.
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