Osteosarcoma‐initiating cells show high aerobic glycolysis and attenuation of oxidative phosphorylation mediated by LIN28B

Emi, Mitsuru; Tsukahara, Tomohide; Emori, Makoto; Murata, Kenji; Akamatsu, Asuka; Shibayama, Yuki; Hamada, Shuto; Watanabe, Yuto; Kaya, Mitsunori; Hirohashi, Yoshihiko; Kanaseki, Takayuki; Nakatsugawa, Munehide; Kubo, Terufumi; Yamashita, Toshihiko; Sato, Noriyuki; Torigoe, Toshihiko

doi:10.1111/cas.14229

Cited by 30 publications

(26 citation statements)

References 26 publications

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“…Another recent manuscript correlates highly in vivo tumorigenic OS cells with great dependence on glycolysis and with the suppression of OXPHOS compared to low tumorigenic ones. In agreement, glycolytic inhibitors combined with chemotherapy reduce tumorigenesis of OS cells, suggesting that glycolysis inhibition combined with chemotherapy might be a promising adjuvant treatment for OS [136].…”

Section: Lactate and Sarcomassupporting

confidence: 55%

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Taddei

Pietrovito

Leo

et al. 2020

Cells

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Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.

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Section: Lactate and Sarcomassupporting

confidence: 55%

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Taddei

Pietrovito

Leo

et al. 2020

Cells

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“…Moreover, various microRNAs regulate both osteosarcoma growth (proliferation) and glycolysis either positively (e.g., miRNA543) [51] or negatively (e.g., miRNA186) [52]. Furthermore, glycolysis also appears to correlate with chemosensitivity (e.g., cisplatin sensitivity [53]) or viability of osteosarcoma cells [54,55].…”

Section: Discussionmentioning

confidence: 99%

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Kiss

Ráduly

Regdon

et al. 2020

Cancers

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Osteosarcoma (OS) is the most common bone tumor in children and adolescents. Modern OS treatment, based on the combination of neoadjuvant chemotherapy (cisplatin + doxorubicin + methotrexate) with subsequent surgical removal of the primary tumor and metastases, has dramatically improved overall survival of OS patients. However, further research is needed to identify new therapeutic targets. Here we report that expression level of the nuclear NAD synthesis enzyme, nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1), increases in U-2OS cells upon exposure to DNA damaging agents, suggesting the involvement of the enzyme in the DNA damage response. Moreover, genetic inactivation of NMNAT1 sensitizes U-2OS osteosarcoma cells to cisplatin, doxorubicin, or a combination of these two treatments. Increased cisplatin-induced cell death of NMNAT1−/− cells showed features of both apoptosis and necroptosis, as indicated by the protective effect of the caspase-3 inhibitor z-DEVD-FMK and the necroptosis inhibitor necrostatin-1. Activation of the DNA damage sensor enzyme poly(ADP-ribose) polymerase 1 (PARP1), a major consumer of NAD+ in the nucleus, was fully blocked by NMNAT1 inactivation, leading to increased DNA damage (phospho-H2AX foci). The PARP inhibitor, olaparib, sensitized wild type but not NMNAT1−/− cells to cisplatin-induced anti-clonogenic effects, suggesting that impaired PARP1 activity is important for chemosensitization. Cisplatin-induced cell death of NMNAT1−/− cells was also characterized by a marked drop in cellular ATP levels and impaired mitochondrial respiratory reserve capacity, highlighting the central role of compromised cellular bioenergetics in chemosensitization by NMNAT1 inactivation. Moreover, NMNAT1 cells also displayed markedly higher sensitivity to cisplatin when grown as spheroids in 3D culture. In summary, our work provides the first evidence that NMNAT1 is a promising therapeutic target for osteosarcoma and possibly other tumors as well.

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“…For example, LIN28B has been identified, using next-generation sequencing (NGS), as a CSC-related gene highly expressed in isolated clones with a higher tumorigenic potential, and as CSC-related protein expressed in 85% of osteosarcoma primary tissues. LIN28 silencing changed the metabolism of cells and induced the loss of CSC traits [65]. Moreover, in sarcoma it has been reported that high expression of LIN28B and survival correlate inversely with each other [66].…”

Section: Stemness Markersmentioning

confidence: 99%

Cancer Stem Cells in Soft-Tissue Sarcomas

Martínez-Delgado

Lacerenza

Obrador‐Hevia

et al. 2020

Cells

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Soft tissue sarcomas (STS) are a rare group of mesenchymal solid tumors with heterogeneous genetic profiles and clinical features. Systemic chemotherapy is the backbone treatment for advanced STS; however, STS frequently acquire resistance to standard therapies, which highlights the need to improve treatments and identify novel therapeutic targets. Increases in the knowledge of the molecular pathways that drive sarcomas have brought to light different molecular alterations that cause tumor initiation and progression. These findings have triggered a breakthrough of targeted therapies that are being assessed in clinical trials. Cancer stem cells (CSCs) exhibit mesenchymal stem cell (MSC) features and represent a subpopulation of tumor cells that play an important role in tumor progression, chemotherapy resistance, recurrence and metastasis. In fact, CSCs phenotypes have been identified in sarcomas, allied to drug resistance and tumorigenesis. Herein, we will review the published evidence of CSCs in STS, discussing the molecular characteristic of CSCs, the commonly used isolation techniques and the new possibilities of targeting CSCs as a way to improve STS treatment and consequently patient outcome.

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Osteosarcoma‐initiating cells show high aerobic glycolysis and attenuation of oxidative phosphorylation mediated by LIN28B

Cited by 30 publications

References 26 publications

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Cancer Stem Cells in Soft-Tissue Sarcomas

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