Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding

DeWitt, Suzanne Bartholf; Plumlee, Sarah Hoskinson; Brighton, Hailey E.; Sivaraj, Dharshan; Martz, E. J.; Zand, Maryam; Kumar, Vardhman; Sheth, Maya U.; Floyd, Robert W.; Spruance, Jacob; Hawkey, Nathan; Varghese, Shyni; Ruan, Jianhua; Kirsch, David G.; Somarelli, Jason A.; Alman, Benjamin A.; Eward, William C.

doi:10.1172/jci.insight.151583

Cited by 9 publications

(7 citation statements)

References 91 publications

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“…Meanwhile, increased NF-κB activity can also promote OS cell proliferation, inhibit OS cell apoptosis, and promote the generation of collateral vessels in OS. [69,70] 3.7. MAPK signaling pathway MAPK pathway is an important central link in multiple signaling pathways, which is mainly involved in regulating cell proliferation, differentiation, apoptosis, cycle arrest, immunity and inflammation.…”

Section: Nf-κb Signaling Pathwaymentioning

confidence: 99%

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Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

Liu,

Jiang,

et al. 2024

Medicine

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Osteosarcoma (OS) has a high recurrence rate, disability rate, mortality and metastasis, it brings great economic burden and psychological pressure to patients, and then seriously affects the quality of life of patients. At present, the treatment methods of OS mainly include radiotherapy, chemotherapy, surgical therapy and neoadjuvant chemotherapy combined with limb salvage surgery. These treatment methods can relieve the clinical symptoms of patients to a certain extent, and also effectively reduce the disability rate, mortality and recurrence rate of OS patients. However, because metastasis of tumor cells leads to new complications, and OS cells become resistant with prolonged drug intervention, which reduces the sensitivity of OS cells to drugs, these treatments still have some limitations. More and more studies have shown that traditional Chinese medicine (TCM) has the characteristics of “multiple targets and multiple pathways,” and can play an important role in the development of OS through several key signaling pathways, including PI3K/AKT, Wnt/β-catenin, tyrosine kinase/transcription factor 3 (JAK/STAT3), Notch, transforming growth factor-β (TGF-β)/Smad, nuclear transcription factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), nuclear factor E2-related factor 2 (Nrf2), Hippo/YAP, OPG/RANK/RANKL, Hedgehog and so on. In this paper, the signaling pathways of cross-interference between active ingredients of TCM and OS were reviewed, and the development status of novel OS treatment was analyzed. The active ingredients in TCM can provide therapeutic benefits to patients by targeting the activity of signaling pathways. In addition, potential strategies for targeted therapy of OS by using ferroptosis were discussed. We hope to provide a unique insight for the in-depth research and clinical application of TCM in the fields of OS growth, metastasis and chemotherapy resistance by understanding the signaling crosstalk between active ingredients in TCM and OS.

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Section: Nf-κb Signaling Pathwaymentioning

confidence: 99%

“…Meanwhile, increased NF-κB activity can also promote OS cell proliferation, inhibit OS cell apoptosis, and promote the generation of collateral vessels in OS. [69,70]…”

Section: Os-associated Signaling Pathwaymentioning

confidence: 99%

Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

Liu,

Jiang,

et al. 2024

Medicine

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“…Notably, alpha thalassemia and intellectual disability syndrome Xlinked (ATRX) deficiency promotes OS cell invasion by increasing NF-κB signaling and integrin β3 binding. 206 The oncogene TRIM10 upregulates nuclear levels of p65, thereby activating classical NF-κB signaling to promote cisplatin resistance in OS cells. 207 Contemporary research on NF-κB-associated mechanisms in OS is centered on the modulation of miRNAs and lncRNAs that are possible upstream modulators of NF-κB and could exert their oncogenic or their inhibitory properties on tumors by affecting the levels of STAT3 expressed in OS cells.…”

Section: Nf-κb Signaling Pathway and Os Development And Progressionmentioning

confidence: 99%

“…reported the inhibition of OS cell metastasis by combining the blockade of integrin β1 expression and NF‐κB signaling in MG63 cells. Notably, alpha thalassemia and intellectual disability syndrome X‐linked (ATRX) deficiency promotes OS cell invasion by increasing NF‐κB signaling and integrin β3 binding 206 . The oncogene TRIM10 upregulates nuclear levels of p65, thereby activating classical NF‐κB signaling to promote cisplatin resistance in OS cells 207 …”

Section: Signaling Pathways In Osmentioning

confidence: 99%

Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies

Shen

Lan

et al. 2023

MedComm

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Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb‐preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challenges in the clinical management of OS. There has been an urgent need to identify new biomarkers for OS to develop specific targeted therapies. Recently, the continued advancements in genomic analysis have contributed to the identification of clinically significant molecular biomarkers for diagnosing OS, acting as therapeutic targets, and predicting prognosis. Additionally, the contemporary molecular classifications have revealed that the signaling pathways, including Wnt/β‐catenin, PI3K/AKT/mTOR, JAK/STAT3, Hippo, Notch, PD‐1/PD‐L1, MAPK, and NF‐κB, have an integral role in OS onset, progression, metastasis, and treatment response. These molecular classifications and biological markers have created new avenues for more accurate OS diagnosis and relevant treatment. We herein present a review of the recent findings for the modulatory role of signaling pathways as possible biological markers and treatment targets for OS. This review also discusses current OS therapeutic approaches, including signaling pathway‐based therapies developed over the past decade. Additionally, the review covers the signaling targets involved in the curative effects of traditional Chinese medicines in the context of expression regulation of relevant genes and proteins through the signaling pathways to inhibit OS cell growth. These findings are expected to provide directions for integrating genomic, molecular, and clinical profiles to enhance OS diagnosis and treatment.

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“…ATRX is an important tumor suppressor in OS, and it is a part of a multiprotein complex that regulates chromatin remodeling, nucleosome assembly, and telomere maintenance. Furthermore, a recent report noted that loss of ATRX promotes OS tumor through increased NF-κB signaling and integrin binding [20]. DLG2 is a tumor suppressor gene, and its copy number loss occurs in 42% of human and 56% of canine OS [21].…”

Section: Inactivation Of Tumor Suppressor Genes and Amplification Of ...mentioning

confidence: 99%

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

Nirala

Yamamichi

Yustein

2023

IJMS

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Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, it has heterogeneous abnormalities, including somatic DNA copy number alteration, ploidy, chromosomal amplification, and chromosomal loss and gain. Unfortunately, clinical outcomes have not significantly improved in over 30 years. Currently, no effective molecularly targeted therapies are available for this disease. Several genomic studies showed inactivation in the tumor suppressor genes, including p53, RB, and ATRX, and hyperactivation of the tumor promoter genes, including MYC and MDM2, in OS. Alterations in the major signaling pathways, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/β-catenin, NOTCH, Hedgehog/Gli, TGF-β, RTKs, RANK/RANKL, and NF-κB signaling pathways, have been identified in OS development and metastasis. Although OS treatment is currently based on surgical excision and systematic multiagent therapies, several potential targeted therapies are in development. This review focuses on the major signaling pathways of OS, and we propose a biological rationale to consider novel and targeted therapies in the future.

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Loss of ATRX promotes aggressive features of osteosarcoma with increased NF-κB signaling and integrin binding

Abstract: DGK is a cofounder of Xrad Therapeutics, which is developing radiosensitizers, and he serves on the Scientific Advisory Board of Lumicell, which is commercializing intraoperative imaging technology.

Cited by 9 publications

References 91 publications

Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

Effect of traditional Chinese medicine in osteosarcoma: Cross-interference of signaling pathways and potential therapeutic targets

Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis

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