Anti-Invasive and Anti-Migratory Effects of Ononin on Human Osteosarcoma Cells by Limiting the MMP2/9 and EGFR-Erk1/2 Pathway

Gong, Guowei; Ganesan, Kumar; Xiong, Qingping; Zheng, Yuzhong

doi:10.3390/cancers15030758

Cited by 15 publications

(16 citation statements)

References 38 publications

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“…The transactivation of EGFR by GPCR agonism is well-described and known to cause downstream activation of MEK/ERK1/2 MAP kinase pathways, which in turn influence invasion and migration capacities of tumor cells [ 34 – 37 ]. Given our results, we hypothesized that FFA1 suppresses pRCC cell invasion via inhibition of EGFR-mediated ERK1/2 signaling in pRCC cells.…”

Section: Resultsmentioning

confidence: 99%

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Karmokar

Moniri

2023

Cancer Cell Int

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Background Papillary renal cell carcinoma (pRCC) is a highly metastatic genitourinary cancer and is generally irresponsive to common treatments used for the more prevalent clear-cell (ccRCC) subtype. The goal of this study was to examine the novel role of the free fatty-acid receptor-1 (FFA1/GPR40), a cell-surface expressed G protein-coupled receptor that is activated by medium-to-long chained dietary fats, in modulation of pRCC cell migration invasion, proliferation and tumor growth. Methods We assessed the expression of FFA1 in human pRCC and ccRCC tumor tissues compared to patient-matched non-cancerous controls, as well as in RCC cell lines. Using the selective FFA1 agonist AS2034178 and the selective FFA1 antagonist GW1100, we examined the role of FFA1 in modulating cell migration, invasion, proliferation and tumor growth and assessed the FFA1-associated intracellular signaling mechanisms via immunoblotting. Results We reveal for the first time that FFA1 is upregulated in pRCC tissue compared to patient-matched non-cancerous adjacent tissue and that its expression increases with pRCC cancer pathology, while the inverse is seen in ccRCC tissue. We also show that FFA1 is expressed in the pRCC cell line ACHN, but not in ccRCC cell lines, suggesting a unique role in pRCC pathology. Our results demonstrate that FFA1 agonism promotes tumor growth and cell proliferation via c-Src/PI3K/AKT/NF-κB and COX-2 signaling. At the same time, agonism of FFA1 strongly inhibits migration and invasion, which are mechanistically mediated via inhibition of EGFR, ERK1/2 and regulators of epithelial–mesenchymal transition. Conclusions Our data suggest that FFA1 plays oppositional growth and migratory roles in pRCC and identifies this receptor as a potential target for modulation of pathogenesis of this aggressive cancer.

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Section: Resultsmentioning

confidence: 99%

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Karmokar

Moniri

2023

Cancer Cell Int

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“…Osteosarcoma is the most common primary malignant tumor of bone with a high risk of recurrence and distant metastasis (Gong et al, 2023). The survival status of osteosarcoma patients was still poor due to drug resistance, recurrence, or metastasis (Wang et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

(E)‐SIS3 suppressed osteosarcoma progression via promoting cell apoptosis, arresting cell cycle, and regulating the tumor immune microenvironment

Huang,

Zhang,

Zhu

et al. 2023

Drug Development Research

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Osteosarcoma is a prevalent malignant bone tumor with a poor prognosis. Mothers against decapentaplegic homolog 3 (Smad3) present as a therapeutic target in antitumor treatment, whereas its functions in the osteosarcoma have not been well explored. In the current study, we aimed to investigate the effects of Smad3 in the progression of osteosarcoma. The tumor immune single‐cell hub 2 website was used for graph‐based visualization of Smad3 status in osteosarcoma single‐cell database. Western Blot was applied to detect the expression of Smad3 protein in cell lines. Colony formation and cell counting kit‐8 assays were used to evaluate cell proliferation. Transwell and wound healing assays were used to detect the migration and invasion abilities of cells. Cell apoptosis rates and cell cycle changes were explored by using flow cytometry analysis. The xenograft tumor growth model was applied to explore the effect in tumor growth after Smad3 blockage in vivo. Moreover, to confirm the potential mechanism of Smad3's effects on osteosarcoma, bioinformatics analysis was performed in TARGET‐Osteosarcoma and GSE19276 databases. Our study found that the Smad3 protein is overexpressed in 143B and U2OS cells, suppressing the expression of Smad3 protein in osteosarcoma cells by Smad3 target inhibitor (E)‐SIS3 or lentivirus can inhibit the proliferation, migration, invasion, promote cell apoptosis, arrest cell G1 cycle in osteosarcoma cells in vitro, and suppress tumor growth in vivo. Furthermore, the bioinformatics analysis demonstrated that high expression of Smad3 is closely associated with low immune status in TARGET‐Osteosarcoma and GSE19276 databases. Our study suggested that Smad3 could contribute positively to osteosarcoma progression via the regulation of tumor immune microenvironment, and Smad3 may represent as an valuable potential therapeutic target in osteosarcoma therapy.

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“…While the five-year survival rate has increased as medical technology has advanced, no significant gain has been achieved [ 4 ]. Recent research has associated the disruption of different intracellular signal pathways with the formation and progression of osteosarcoma [ 5 , 6 ]. It is critical to investigate the signal pathways involved in the incidence, progression, and therapy of osteosarcoma [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Hydroxysafflor yellow A induced ferroptosis of Osteosarcoma cancer cells by HIF-1α/HK2 and SLC7A11 pathway

ZHU,

YANG,

et al. 2024

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Osteosarcoma is a very serious primary bone cancer with a high death rate and a dismal prognosis. Since there is no permanent therapy for this condition, it is necessary to develop a cure. Therefore, this investigation was carried out to assess the impacts and biological functions of hydroxysafflor yellow A (HYSA) in osteosarcoma cell lines (MG63). In this investigational study, MG63 cells were utilized. Microarray experiments, quantitative polymerase chain reaction (qPCR), immunofluorescent staining, extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose consumption, lactate production, and ATP levels, proliferation assay, 5-Ethynyl-2′-deoxyuridine (EDU) staining, and Western blot were performed. In MG63 cells, HYSA lowered cell proliferation and metastasis rates, suppressed EDU cell number, and enhanced caspase-3/9 activity levels. HYSA reduced the Warburg effect and induced ferroptosis (FPT) in MG63 cells. Inhibiting ferroptosis diminished HYSA’s anti-cancer activities in MG63 cells. The stimulation of the HIF-1α/SLC7A11 pathway decreased HYSA’s anti-cancer activities in MG63 cells. HIF-1α is one target spot for HYSA in a model of osteosarcoma cancer (OC). HYSA altered HIF-1α’s thermophoretic activity; following binding with HYSA, HIF-1α’s melting point increased from ~55°C to ~60°C. HYSA significantly enhanced the thermal stability of exogenous WT HIF-1α while not affecting Mut HIF-1α, suggesting that ARG-311, GLY-312, GLN-347, and GLN-387 may be involved in the interaction between HIF-1α and HYSA. Conclusively, our study revealed that HYSA induced FPT and reduced the Warburg effect of OC through mitochondrial damage by HIF-1α/HK2/SLC7A11 pathway. HYSA is a possible therapeutic option for OC or other cancers.

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Anti-Invasive and Anti-Migratory Effects of Ononin on Human Osteosarcoma Cells by Limiting the MMP2/9 and EGFR-Erk1/2 Pathway

Cited by 15 publications

References 38 publications

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

Free-fatty acid receptor-1 (FFA1/GPR40) promotes papillary RCC proliferation and tumor growth via Src/PI3K/AKT/NF-κB but suppresses migration by inhibition of EGFR, ERK1/2, STAT3 and EMT

(E)‐SIS3 suppressed osteosarcoma progression via promoting cell apoptosis, arresting cell cycle, and regulating the tumor immune microenvironment

Hydroxysafflor yellow A induced ferroptosis of Osteosarcoma cancer cells by HIF-1α/HK2 and SLC7A11 pathway

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