Basic fibroblast growth factor promotes doxorubicin resistance in chondrosarcoma cells by affecting XRCC5 expression

Abstract

Chondrosarcoma is the second most common form of bone cancer and is characterized by its ability to produce an extracellular matrix of the cartilage. High‐grade chondrosarcoma is highly aggressive and can metastasize to other parts of the body. Chondrosarcoma is resistant to both conventional chemotherapy and radiotherapy; hence, the current main treatment is still surgical resection. Doxorubicin (Dox) has been shown to significantly improve patient survival compared with untreated chondrosarcoma. However, for patients with metastasis, surgical resection alone can hardly treat them. In addition, drug resistance is one of the leading causes of death in patients with chondrosarcoma. Secreted proteins can mediate cell‐cell interactions in the cancer microenvironment, which may be associated with the development of drug resistance. In the present study, chondrosarcoma cells were treated with Dox, the conditioned medium was then collected and changes in secreted proteins were analyzed using the antibody array. Results showed that the Dox‐treated group had the highest secretion of basic fibroblast growth factor (bFGF), indicating the effect of bFGF on Dox sensitivity in chondrosarcoma. Furthermore, lentiviral‐mediated knockdown and treatment of exogenous recombinant protein were employed to further investigate the effect of bFGF on Dox resistance. Results demonstrated that bFGF can promote the expression of X‐ray repair cross‐complementing protein 5 (XRCC5), leading to Dox resistance. Secreted bFGF is likely to be detected in serum, in addition to being a biomarker for predicting Dox resistance, the combination of Dox and bFGF/XRCC5 blockers may be a new therapeutic strategy to improve the efficacy of Dox in future.

FGF/FGFR-Dependent Molecular Mechanisms Underlying Anti-Cancer Drug Resistance

“…The increasing number of cases correlating FGF and FGFR expression in cancer cells with treatment failure and poor patient prognosis highlights the important role of these proteins in the cellular response to anti-cancer drugs. FGFs and FGFRs have been associated with resistance to several cytotoxic agents, such as paclitaxel, cisplatin, etoposide, 5-fluorouracil, doxorubicin, and others in various tumor types ( Table 1 ) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. Most studies on the involvement of FGF proteins in the development of drug resistance involve FGF1 and FGF2, while there are a few reports on the role of other FGFs in this process, including FGF4, FGF5, FGF9, FGF10, FGF13, and FGF19 [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

Addressing Doxorubicin Resistance in Bone Sarcomas Using Novel Drug-Resistant Models

“…To contribute to this objective, we have developed and functionally characterized a panel of four bone sarcoma cell lines resistant to DOX. These models expand the still scarce panel of DOX-resistant osteosarcoma and chondrosarcoma cell lines available [ 14 , 23 , 37 , 38 , 39 , 40 , 41 ]. To the best of our knowledge, this is the first study describing the generation of DOX-resistant models developed from a chondrosarcoma patient-derived cell line.…”

Co-transfection with BMP2 and FGF2 via chitosan nanoparticles potentiates osteogenesis in human adipose-derived stromal cells in vitro

“… 40 Other BMP family proteins, including BMP-9, can also promote osteoblastic differentiation of MSCs both in vitro and in vivo , but probably via different mechanisms. 41 FGF2 is a polypeptide that promotes cell growth and bone tissue repair, and exogenous FGF2 was shown to promote bone formation; 42 however, exogenous FGF2 is easily degraded within the body, thus reducing its efficacy. 43 The FGF2 gene can now be transfected into osteoblasts, leading to over-expression of FGF2 protein and the promotion of osteogenesis in vivo .…”