Emetine elicits apoptosis of intractable B-cell lymphoma cells with <i>MYC</i> rearrangement through inhibition of glycolytic metabolism

Aoki, Tomohiro; Shimada, Kazuyuki; Sakamoto, Akihiko; Sugimoto, Kazunori; Morishita, Takanobu; Kojima, Yoshiyuki; Shimada, Satoko; Kato, Seiichi; Iriyama, Chisako; Kuno, Susumu; Harada, Yoshio; Tomita, Akihiro; Hayakawa, Fumihiko; Kiyoi, Hitoshi

doi:10.18632/oncotarget.14393

Cited by 18 publications

(16 citation statements)

References 41 publications

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“…We have previously reported that the BLS4 mouse FRC line, which was established from a mouse lymph node, enabled culture of PDX lymphoma cells and that CAF also supported survival of primary patient lymphoma cells in vitro . Primary patient lymphoma cells (Pt#8 with Burkitt lymphoma, and Pt#9 with high‐grade B‐cell lymphoma, not otherwise specified) could proliferate in coculture with CAF#1 and CAF#2 in vitro, whereas neither cell type could survive in monoculture (Figure A,B; Table ).…”

Section: Resultsmentioning

confidence: 96%

“…Generally, the TME is known to be under hypoxic conditions and promotes a metabolic switch in tumor cells away from mitochondrial respiration to glycolysis . According to our previous report, tumor cells in coculture with CAF promote anaerobic glycolysis as indicated by the increased expressions of HK2 and PDK1 . Considering the complexity in terms of energy production in tumor cells, tumor cells might coordinate the regulation of aerobic glycolysis and the citric acid cycle according to the specific TME .…”

Section: Discussionmentioning

confidence: 99%

“…Patient‐derived CAF were established as described previously . In brief, residue from a fresh patient sample mashed to obtain a cell suspension for diagnostic analyses was loosened in 0.25% trypsin‐EDTA solution, then placed into a 10‐cm dish with Iscove's modified Dulbecco's medium (Sigma‐Aldrich, St Louis, MO, USA) supplemented with 10% FBS (Gibco in Thermo Fisher Scientific, Waltham, MA, USA) and 2 mmol/L glutamine (Gibco).…”

Section: Methodsmentioning

confidence: 99%

“…In the TME of various tumors, humoral factors released from CAF play fundamental roles in tumor metastasis, resistance to chemotherapy, and epithelial‐to‐mesenchymal transition (EMT) . In malignant lymphoma, we have previously reported that a mouse‐derived fibroblastic reticular cell (FRC) line supported lymphoma cells from patient‐derived xenograft (PDX) models, indicating that fibroblasts also play many functional roles in the lymphoma microenvironment . This report examined how CAF isolated from primary lymphoma samples support primary lymphoma cells in vitro and clarified the components vital for these abilities.…”

Section: Introductionmentioning

confidence: 99%

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Pyruvate secreted from patient‐derived cancer‐associated fibroblasts supports survival of primary lymphoma cells

et al. 2018

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Cancer‐associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor‐cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse‐Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pyruvate secreted from patient‐derived cancer‐associated fibroblasts supports survival of primary lymphoma cells

et al. 2018

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“…MAPK signaling is a complicated process involved in the pathogenesis of human disorders ranging from cancers and neurodegenerative diseases. The stimulation of MAPK cascades leads to disease development by initiating neuronal apoptosis (34). Inhibitors of ERK1/2, MEK, JNK, and p38 MAPK are considered to be potential drugs for many diseases including cancer (35).…”

Section: O21mentioning

confidence: 99%

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

2020

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Lung cancer is the most prevalent in cancer-related deaths, while breast carcinoma is the second most dominant cancer in women, accounting for the most number of deaths worldwide. Cancers are heterogeneous diseases that consist of several subtypes based on the presence or absence of hormone receptors and human epidermal growth factor receptor 2. Several drugs have been developed targeting cancer biomarkers; nonetheless, their efficiency are not adequate due to the high reemergence rate of cancers and fundamental or acquired resistance toward such drugs, which leads to partial therapeutic possibilities. Recent studies on cardiac glycosides (CGs) positioned them as potent cytotoxic agents that target multiple pathways to initiate apoptosis and autophagic cell death in many cancers. In the present study, our aim is to identify the anticancer activity of a naturally available CG (strophanthidin) in human breast (MCF-7), lung (A549), and liver cancer (HepG2) cells. Our results demonstrate a dose-dependent cytotoxic effect of strophanthidin in MCF-7, A549, and HepG2 cells, which was further supported by DNA damage on drug treatment. Strophanthidin arrested the cell cycle at the G2/M phase; this effect was further validated by checking the inhibited expressions of checkpoint and cyclin-dependent kinases in strophanthidin-induced cells. Moreover, strophanthidin inhibited the expression of several key proteins such as MEK1, PI3K, AKT, mTOR, Gsk3α, and β-catenin from MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. The current study adequately exhibits the role of strophanthidin in modulating the expression of various key proteins involved in cell cycle arrest, apoptosis, and autophagic cell death. Our in silico studies revealed that strophanthidin can interact with several key proteins from various pathways. Taken together, this study demonstrates the viability of strophanthidin as a promising anticancer agent, which may serve as a new anticancer drug.

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Up‐regulation of TNF‐alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma

de Castro,

de Oliveira,

Milan

et al. 2023

Journal Cellular Physiology

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Tumor resistance remains an obstacle to successfully treating oral squamous cell carcinoma (OSCC). Cisplatin is widely used as a cytotoxic drug to treat solid tumors, including advanced OSCC, but with low efficacy due to chemoresistance. Therefore, identifying the pathways that contribute to chemoresistance may show new possibilities for improving the treatment. This work explored the role of the tumor necrosis factor‐alpha (TNF‐alpha)/NFkB signaling in driving the cisplatin resistance of OSCC and its potential as a pharmacological target to overcome chemoresistance. Differential accessibility analysis demonstrated the enrichment of opened chromatin regions in members of the TNF‐alpha/NFkB signaling pathway, and RNA‐Seq confirmed the upregulation of TNF‐alpha/NFkB signaling in cisplatin‐resistant cell lines. NFkB was accumulated in cisplatin‐resistant cell lines and in cancer stem cells (CSC), and the administration of TNF‐alpha increased the CSC, suggesting that TNF‐alpha/NFkB signaling is involved in the accumulation of CSC. TNF‐alpha stimulation also increased the histone deacetylases HDAC1 and SIRT1. Cisplatin‐resistant cell lines were sensitive to the pharmacological inhibition of NFkB, and low doses of the NFkB inhibitors, CBL0137, and emetine, efficiently reduced the CSC and the levels of SIRT1, increasing histone acetylation. The NFkB inhibitors decreased stemness potential, clonogenicity, migration, and invasion of cisplatin‐resistant cell lines. The administration of the emetine significantly reduced the tumor growth of cisplatin‐resistant xenograft models, decreasing NFkB and SIRT1, increasing histone acetylation, and decreasing CSC. TNF‐alpha/NFkB/SIRT1 signaling regulates the epigenetic machinery by modulating histone acetylation, CSC, and aggressiveness of cisplatin‐resistant OSCC and the NFkB inhibition is a potential strategy to treat chemoresistant OSCC.

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Emetine elicits apoptosis of intractable B-cell lymphoma cells with MYC rearrangement through inhibition of glycolytic metabolism

Cited by 18 publications

References 41 publications

Pyruvate secreted from patient‐derived cancer‐associated fibroblasts supports survival of primary lymphoma cells

Pyruvate secreted from patient‐derived cancer‐associated fibroblasts supports survival of primary lymphoma cells

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

Up‐regulation of TNF‐alpha/NFkB/SIRT1 axis drives aggressiveness and cancer stem cells accumulation in chemoresistant oral squamous cell carcinoma

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