Far upstream element‐binding protein 1 confers lobaplatin resistance by transcriptionally activating PTGES and facilitating the arachidonic acid metabolic pathway in osteosarcoma

Abstract

Drug resistance is a major obstacle in cancer treatment and recurrence prevention and leads to poor outcomes in patients suffering from osteosarcoma. Clarification of the mechanism of drug resistance and exploration of effective strategies to overcome this obstacle could lead to clinical benefits for these patients. The expression of far upstream element‐binding protein 1 (FUBP1) was found to be markedly elevated in osteosarcoma cell lines and clinical specimens compared with osteoblast cells and normal bone specimens. High expression of FUBP1 was correlated with a more aggressive phenotype and a poor prognosis in osteosarcoma patients. We found that overexpression of FUBP1 confers lobaplatin resistance, whereas the inhibition of FUBP1 sensitizes osteosarcoma cells to lobaplatin‐induced cytotoxicity both in vivo and in vitro. Chromatin immunoprecipitation‐seq and RNA‐seq were performed to explore the potential mechanism. It was revealed that FUBP1 could regulate the transcription of prostaglandin E synthase (PTGES) and subsequently activate the arachidonic acid (AA) metabolic pathway, which leads to resistance to lobaplatin. Our investigation provides evidence that FUBP1 is a potential therapeutic target for osteosarcoma patients. Targeting FUBP1, its downstream target PTGES and the AA metabolic pathway may be promising strategies for sensitizing chemoresistant osteosarcoma cells to lobaplatin.

Multimodal Mass Spectrometry Imaging of an Osteosarcoma Multicellular Tumour Spheroid Model to Investigate Drug-Induced Response

“…The increased localisation of m / z 303.23203 (FA 20:4, e.g., AA) in the tumour model core ( Figure 1 a(iii)) is of interest given that AA, a polyunsaturated fatty acid (PUFA), and its metabolism are focal points of many drug development targets due to the implications for AA and its metabolites in pathways such as mTOR [ 41 ], MAPK [ 42 , 43 ] and PI3K [ 44 , 45 ]. A recent study found an upregulation of AA to be a target of OS with promising potential to chemosensitise OS cells given that far upstream element-binding protein 1 (FUBP1) was shown to be upregulated in OS cells and associated with a poorer clinical prognosis [ 46 ]. FUBP1 upregulates the AA metabolic pathway, and therefore AA and its metabolites are potential targets for increasing chemosensitivity and overcoming chemoresistance in OS.…”

Icariin activates far upstream element binding protein 1 to regulate hypoxia-inducible factor-1α and hypoxia-inducible factor-2α signaling and benefits chondrocytes

“…Far upstream element binding protein 1 (FUBP1), containing 644 amino acids and having helicase activity, is responsible for regulating cell proliferation by targeting c-Myc ( Ma et al, 2020 ). FUBP1 is known to participate in the malignant process and glycolysis of colon cancer cells by combining with c-Myc ( Wang et al, 2022 ).…”