2‐Methoxyestradiol‐Mediated Induction of Frzb Contributes to Cell Death and Autophagy in MG63 Osteosarcoma Cells

Bravo, Dalibel; Shogren, Kristen L.; Zuo, Dongqing; Wagner, Eric R.; Sarkar, Gobinda; Yaszemski, Michael J.; Maran, Avudaiappan

doi:10.1002/jcb.25809

Cited by 16 publications

(16 citation statements)

References 48 publications

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“…Herein, we observed that the induction of autophagy by 2-ME was strictly correlated with the inhibition of proliferation and migration and the induction of apoptosis in osteosarcoma cells. The correlation of the induction of autophagy by 2-ME with the induction of cell death has previously been demonstrated in various experimental models including osteosarcoma cells (60,61). Moreover, it has been suggested the molecular crosstalk between 2-ME-induced apoptosis and autophagy is associated with its impact on microtubule integrity in cervical adenocarcinoma cells (62).…”

Section: Discussionmentioning

confidence: 90%

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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Abstract. Background Cancer cells are traditionally characterized by increased glucose uptake, high rates of aerobic glycolysis, increased lactic acid production, impaired mitochondrial function and decreased extracellular pH. These characteristics are known as the 'Warburg effect' (1-3). The 'Warburg effect' is also observed in cancer-associated fibroblasts and mesenchymal stem cells (1-11), which secrete lactate and ketones into the microenvironment of the tumor. Lactic acid exists as L-and D-optical isomers. In mammals including humans, lactate is present almost entirely as L-lactate (12, 13). Interestingly, a variety of human cancer cell lines and human tumors, including breast, prostate, head, neck, and osteosarcoma cancers, import these metabolites and deliver them to the mitochondrial TCA cycle, thereby promoting ATP generation and cell proliferation (1-14). According to this 'reverse Warburg effect', tumor cells can induce metabolic reprogramming by shuttling lactate as an energy source to neighboring cancer cells, to the adjacent stroma and to vascular endothelial cells (1,14).Tumors contain both aerobic and hypoxic regions that form a metabolic symbiosis that is crucial for tumor cell survival (15, 16). The cancer cells located in the hypoxic regions export lactate, which acidifies the tumor environment; the cells located in the aerobic regions, however, import lactate and utilize it for oxidative phosphorylation (4). Bonuccelli and colleagues (2) suggested that L-lactate metabolism in cancer cells may explain why diabetic patients have an increased risk of cancer development and a tendency towards autophagy/mitophagy in their adipose tissue. An increased tumor L-lactate level strictly correlates with increased metastasis, tumor recurrence and poor outcome (6-9).L-lactate metabolism and the reverse Warburg effect has been clearly established in osteosarcoma cells. It has been demonstrated that the secretion of lactate and ketones by the mesenchymal stem cells drives mitochondrial biogenesis and increases the mitochondrial activity in osteosarcoma cells (1, 483 This article is freely accessible online.Correspondence to: Magdalena Gorska-Ponikowska (MGP),

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Section: Discussionmentioning

confidence: 90%

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Górska‐Ponikowska

Kuban–Jankowska

Daca

et al. 2017

CGP

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“…Human multidrug-resistant cell line U2OSR is a kind gift from Dr. Zhenfeng Duan’s laboratory (University of California, Los Angeles, CA, USA). Cells were cultured in DMEM/F12 medium and maintained at 37 °C [ 16 , 17 ].…”

Section: Methodsmentioning

confidence: 99%

“…Cell lysis and preparation of cytoplasmic protein extract were carried out as described by 2 reports [ 16 , 19 ]. Briefly, cells were resuspended with lysis buffer (0.15 M NaCl, 5 mM EDTA, 10 mM Tris-Cl, 1% Triton X-100), and protein concentrations were determined by Bradford assay.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

Zuo

Shogren

Zang

et al. 2018

J Exp Clin Cancer Res

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BackgroundOsteosarcoma is the most common bone cancer. Despite advances, molecular mechanisms associated with osteosarcoma have not been fully understood. Hence, an effective treatment for osteosarcoma has yet to be developed. Even though signal transducer and activator of transcription3 (STAT3) has been implicated, its role in pathogenesis of osteosarcoma is not fully determined. In this study, we investigated the antitumor effect of napabucasin (NP) (BBI608), an inhibitor of STAT3 on osteosarcoma in vitro and in vivo and studied the underlying molecular mechanism.MethodsCell viability, colony formation, apoptosis, tumor growth and metastasis assays were performed to examine the effect of NP on osteosarcoma in vitro and in vivo. Real-time RT-PCR, western analysis, immunofluorescence and reporter assays were used to monitor the expression and activity of proteins and underlying molecular pathways. Protein synthesis, co-immunoprecipitation and CAP binding assays were carried out to understand NP-mediated mechanism of actions in osteosarcoma cells.ResultsOur results show that NP treatment decreases cell viability and induces apoptosis in several osteosarcoma cell lines. NP treatment suppresses both expression and phosphorylation of STAT3 in addition to blocking STAT3-mediated transcription and downstream target proteins in osteosarcoma cells. Furthermore, NP inhibits protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E-binding protein 1 (4E-BP1). NP also inhibits the progression of osteosarcoma tumors and metastasis in vivo in an orthotopic tibial model of osteosarcoma.ConclusionsTaken together, our investigation reveals that NP acts through a novel mechanism and inhibits osteosarcoma growth and metastasis, and could be investigated clinically for treating osteosarcoma patients alone or in combination with other drugs.

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“…Moreover, autophagy and apoptosis induced by 2-ME were decreased by FRZB/sFRP3 siRNA. Altogether, this suggested the potential use of FRZB/sFRP3 in osteosarcoma [83]. In 2018, the same team analyzed the sera of 67 osteosarcoma and age-matched nondisease controls and observed that the level of FRZB/sFRP3 was lower in osteosarcoma samples.…”

Section: Using Sfrps In Cancer Therapy?mentioning

confidence: 97%

Secreted Frizzled‐related proteins (sFRPs) in osteo‐articular diseases: much more than simple antagonists of Wnt signaling?

2019

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Osteo‐articular diseases are characterized by a dysregulation of joint and/or bone homeostasis. These include diseases affecting the joints originally, such as osteoarthritis and rheumatoid arthritis, or the bone, such as osteoporosis. Inflammation and the involvement of Wingless‐related integration site (Wnt) signaling pathways are key pathophysiological features of these diseases resulting in tissue degradation by matrix‐degrading enzymes, namely matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTs), secreted by the joint resident cells and/or by infiltrating immune cells. Activation of Wnt signaling pathways is modulated by different families of proteins, including Dickkopfs and the secreted Frizzled‐related proteins (sFRPs). The sFRP family is composed of five secreted glycoproteins in mammals that regulate Wnt signaling in the extracellular compartment. Indeed, sFRPs are able to bind both to the soluble Wnt ligands and to their cell membrane receptors, the Frizzled proteins. Their expression profile is altered in osteo‐articular diseases, suggesting that they could account for the abnormal activation of Wnt pathways. In the present article, we review how sFRPs are more than simple antagonists of the Wnt signaling pathways and discuss their pathophysiological relevance in the context of osteo‐articular diseases. We detail their Wnt‐dependent and their Wnt‐independent roles, with a particular emphasis on their ability to modulate the inflammatory response and extracellular matrix (ECM) remodeling. We also discuss their potential therapeutic use with a focus on bone remodeling, osteo‐articular cancers, and tissue engineering.

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2‐Methoxyestradiol‐Mediated Induction of Frzb Contributes to Cell Death and Autophagy in MG63 Osteosarcoma Cells

Cited by 16 publications

References 48 publications

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Inhibition of STAT3 blocks protein synthesis and tumor metastasis in osteosarcoma cells

Secreted Frizzled‐related proteins (sFRPs) in osteo‐articular diseases: much more than simple antagonists of Wnt signaling?

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