Key Takeaways & Executive Findings
- •• FOXM1 is highly expressed in osteosarcoma tissues and methotrexate-resistant cells, contributing to drug resistance. • FOXM1 promotes methotrexate resistance by enhancing autophagy via the HMMR/ATG7 pathway. • Silencing FOXM1 or inhibiting autophagy reverses methotrexate resistance in osteosarcoma cells. • Targeting FOXM1 or autophagy represents a promising strategy to improve osteosarcoma chemotherapy outcomes.
Abstract
Osteosarcoma (OS) is a primary bone cancer mostly found in adolescents and elderly individuals. The treatment of OS is still largely dependent on traditional chemotherapy. However, the high incidence of drug resistance remains one of the greatest impediments to limiting improvements in OS treatment. Recent findings have indicated that the transcription factor FOXM1 plays an important role in various cancer-related events, especially drug resistance. However, the possible role of FOXM1 in the resistance of OS to methotrexate (MTX) remains to be explored. Here, we find that FOXM1, which confers resistance to MTX, is highly expressed in OS tissues and MTX-resistant cells. FOXM1 overexpression promotes MTX resistance by enhancing autophagy in an HMMR/ATG7-dependent manner. Importantly, silencing of FOXM1 or inhibiting autophagy reverses drug resistance. These findings demonstrate a new mechanism for FOXM1-induced MTX resistance and provide a promising target for improving OS chemotherapy outcomes.
1. Introduction
Osteosarcoma (OS) is a rare primary bone cancer that is mostly diagnosed in adolescents and elderly individuals [1]. OS can occur in any bone in the body [2]. The age-adjusted incidence of OS in children and adolescents aged 0 to 24 years is 4.4 per million people annually [3]. Children aged 0 to 9 years have the best overall 5-year relative survival rate (71.8%), followed by adolescents aged 10 to 24 years (65.9%) [1]. Elderly individuals >60 years of age have the worst overall 5-year relative survival rate, at 33.1% [1]. OS is a highly fatal disease due to the high incidence of pulmonary metastases until systemic chemotherapy is combined with surgery [4]. Doxorubicin, methotrexate (MTX), cisplatin, and ifosfamide have been suggested to be the most efficacious agents for treating OS. These drugs are commonly applied in combination with at least three of them to achieve the best outcomes [4]. However, it has been revealed that adding more agents to the treatment regimen does not lead to further benefits [5].
In addition, drug resistance is a major hurdle that severely limits the improvement of OS treatment [6]. The antifolate drug MTX can promote apoptosis mainly by binding to the dihydrofolate reductase enzyme to inhibit DNA synthesis and replication and is widely used to treat rheumatoid arthritis and many cancers, including OS. However, OS may acquire resistance to MTX treatment through a variety of mechanisms, such as increased expression of dihydrofolate reductase enzyme, the folate carrier SLC19A1, and ABC transporters [6]. Identifying novel drug resistance mechanisms may provide new therapeutic targets and further improve OS chemotherapy outcomes.
FOXM1, a member of the forkhead box protein family, is a crucial transcription factor that regulates multiple activities of cancer cells, such as growth, metastasis, recurrence, and stem cell features [7]. Recent findings have indicated the importance of FOXM1 in the modulation of chemotherapeutic resistance in many cancers [8–11]. FOXM1 expression is significantly increased in osteosarcoma [12,13], and FOXM1 decreases tumor formation [14], proliferation, migration, and invasion [13]. Moreover, FOXM1 can induce chemoresistance to cisplatin treatment in OS by activating the expression of multidrug resistance protein 1 [15]. Downregulating FOXM1 expression enhances the sensitivity of OS to cisplatin [16]. FOXM1 is emerging as an attractive target for overcoming chemotherapeutic drug resistance [17]. However, whether FOXM1 participates in the development of MTX resistance in OS remains to be investigated.
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Luoyang Wang, Dongchang Zhai, Lei Tang, Hui Zhang, Xinlong Wang, Ning Ma, Xiaoyue Zhang, Mingguo Cheng, Ruowu Shen (2026). FOXM1 mediates methotrexate resistance in osteosarcoma cells by promoting autophagy. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024084
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Frequently Asked Questions
What is the role of FOXM1 in osteosarcoma methotrexate resistance?
FOXM1 is highly expressed in osteosarcoma tissues and methotrexate-resistant cells, and it promotes methotrexate resistance by enhancing autophagy via the HMMR/ATG7 pathway.
How does FOXM1 promote autophagy in osteosarcoma cells?
FOXM1 induces the expression of HMMR, which in turn activates autophagy through ATG7, leading to increased autophagy and protection of osteosarcoma cells from methotrexate-induced apoptosis.
Can silencing FOXM1 reverse methotrexate resistance in osteosarcoma?
Yes, silencing FOXM1 or inhibiting autophagy reverses methotrexate resistance, enhancing the sensitivity of osteosarcoma cells to methotrexate.
What is the clinical significance of this study?
The study identifies FOXM1 and autophagy as promising therapeutic targets to overcome methotrexate resistance and improve chemotherapy outcomes in osteosarcoma patients.
What are the key mechanisms of methotrexate resistance in osteosarcoma?
Known mechanisms include increased expression of dihydrofolate reductase, the folate carrier SLC19A1, and ABC transporters. This study adds FOXM1-mediated autophagy as a novel mechanism.
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