Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

Pandya, Pankita H.; Cheng, Lijun; Saadatzadeh, M. Reza; Bijangi-Vishehsaraei, Khadijeh; Tang, Shan; Sinn, Anthony L.; Trowbridge, Melissa A.; Coy, Kathryn L.; Bailey, Barbara J.; Young, Courtney; Ding, Junhua; Dobrota, Erika; Dyer, Savannah; Elmi, Adily; Thompson, Quinton; Barghi, Farinaz; Shultz, Jeremiah; Albright, Eric A.; Shannon, Harlan E.; Murray, Mary Ellen; Marshall, Mark S.; Ferguson, Michael J.; Bertrand, Todd; Wurtz, L. Daniel; Batra, Sandeep; Li, Lang; Renbarger, Jamie L.; Pollok, Karen E.

doi:10.3390/cancers12092426

Cited by 12 publications

(5 citation statements)

References 109 publications

(189 reference statements)

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“…In multiple preclinical models of pediatric cancer, CHK1 inhibitor monotherapy was considered sufficient to overcome innate resistance or prevent acquired resistance. In OS, the therapy targeting CHK1, whether monotherapy or synergistic therapy, is regarded as a feasible strategy to overcome the difficulties encountered with chemotherapy (Heidler et al 2020 ; Pandya, et al 2020 ). In this study, after treatment with HMA, downregulated MYC decreased CHK1 expression at the transcriptional level, resulting in the inhibition of the RAD51-mediated homologous recombination process.…”

Section: Discussionmentioning

confidence: 99%

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis

Jing

Chen

Zhang

et al. 2023

Mol Med

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Background Osteosarcoma is a malignant bone tumor that usually affects adolescents aged 15–19 y. The DNA damage response (DDR) is significantly enhanced in osteosarcoma, impairing the effect of systemic chemotherapy. Targeting the DDR process was considered a feasible strategy benefitting osteosarcoma patients. However, the clinical application of DDR inhibitors is not impressive because of their side effects. Chinese herbal medicines with high anti-tumor effects and low toxicity in the human body have gradually gained attention. 2-Hydroxy-3-methylanthraquinone (HMA), a Chinese medicine monomer found in the extract of Oldenlandia diffusa, exerts significant inhibitory effects on various tumors. However, its anti-osteosarcoma effects and defined molecular mechanisms have not been reported. Methods After HMA treatment, the proliferation and metastasis capacity of osteosarcoma cells was detected by CCK-8, colony formation, transwell assays and Annexin V-fluorescein isothiocyanate/propidium iodide staining. RNA-sequence, plasmid infection, RNA interference, Western blotting and immunofluorescence assay were used to investigate the molecular mechanism and effects of HMA inhibiting osteosarcoma. Rescue assay and CHIP assay was used to further verified the relationship between MYC, CHK1 and RAD51. Results HMA regulate MYC to inhibit osteosarcoma proliferation and DNA damage repair through PI3K/AKT signaling pathway. The results of RNA-seq, IHC, Western boltting etc. showed relationship between MYC, CHK1 and RAD51. Rescue assay and CHIP assay further verified HMA can impair homologous recombination repair through the MYC-CHK1-RAD51 pathway. Conclusion HMA significantly inhibits osteosarcoma proliferation and homologous recombination repair through the MYC-CHK1-RAD51 pathway, which is mediated by the PI3K-AKT signaling pathway. This study investigated the exact mechanism of the anti-osteosarcoma effect of HMA and provided a potential feasible strategy for the clinical treatment of human osteosarcoma. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis

Jing

Chen

Zhang

et al. 2023

Mol Med

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“…MG63 and U2OS human OS cell lines (#86051601-1VL and #92022711-1VL, Sigma, St Louis, MO, USA), and a patient-derived xenograft (PDX) TT2-77 xenoline were grown in DMEM ( Pandya et al, 2020 ). Human MSCs (#PT-2501, Lonza, Basel, Switzerland) and human aMSCs (#SCC038, Sigma) were grown in MSCBM (#PT-3238, Lonza).…”

Section: Methodsmentioning

confidence: 99%

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

Huo

Dimmitt

et al. 2023

eLife

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Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of CALR transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.

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“…MG63 and U2OS human OS cell lines (#86051601-1VL and #92022711-1VL, Sigma, St. Louis, MO, USA), and a patient-derived xenograft (PDX) TT2-77 xenoline were grown in DMEM (Pandya et al, 2020). Human mesenchymal stem cells (MSCs) (#PT-2501, Lonza, Basel, Switzerland) and human adipose-derived MSCs (#SCC038, Sigma) were grown in MSCBM (#PT-3238, Lonza).…”

Section: Methodsmentioning

confidence: 99%

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

Huo

Dimmitt

et al. 2022

Preprint

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Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and osteosarcoma-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with Cisplatin. CM was enriched with proteins such as Calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of Calr transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein (APP), a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.

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Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

Cited by 12 publications

References 109 publications

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis

2-Hydroxy-3-methylanthraquinone inhibits homologous recombination repair in osteosarcoma through the MYC-CHK1-RAD51 axis

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

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