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Tumor Suppression Efficacy of Heat Shock Protein 90 Inhibitor 17AAG in a Liposarcoma Mouse Model
Seunghoon Nam1,2, Hyungjoon Kim2, Doopyo Hong2
1Department of Health Sciences & Technology, Graduate School, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.
Background/Aim:
Heat shock protein 90 (HSP90) inhibitors have recently been tested as anticancer drugs in a variety of carcinomas. Yet, there exist only few reports about HSP90 inhibitor and its thepeutic effect on liposarcoma. The therapeutic effects of HSP90 inhibitors have been mainly observed in oncogenic and tumor angiogenic signaling cascades by observing tumor growth.
Materials And Methods:
We used the the LPS 246 liposarcoma cell line and GS-076 PDC (patient-derived cell lines). On these, we performed cell viability assays and migration assays under treatment with the HSP90 inhibitor, 17AAG. For analyzing angiogenesis factor, we used quantitative polymerase chain reaction (qPCR) after treating cells with the 17AAG inhibitor. Regarding in vivo assay, we made the tumor model in immune-deficient mouse and compared the tumor size of drug-treated group at each time point with controls. For sequestering analysis of angiogenesis factor in vivo, we performed immuno-fluorescence (IF) staining on tumor tissue.
Results:
Through cell viability, migration assay and qPCR about angiogenesis factor, we demonstrated the anti-oncogenic and anti-angiogenic effects of an HSP90 inhibitor on a liposarcoma cell line and a patient-derived primary cell model (PDC). Also, the HSP90 inhibitor 17AAG effectively inhibited the activity of protein kinase B (AKT) and blocked extracellular signal-regulated kinase (ERK) activity. Hence, 17AAG effectively disrupted the oncogenic signaling cascade and substantially inhibited tumor growth in vitro. In an LPS 863 cell xenograft mouse model treated with 17AAG, we observed that tumor size was decreasing, as well as down-regulation of the expression levels of vascular endothelial growth factor receptor 2 (VEGFR2), CD31 and signal transducer and activator of transcription-3 (STAT3).
Conclusion:
17AAG reduced the activity of AKT, ERK, VEGF and STAT3 in oncogenic and angiogenic pathways in liposarcoma PDC models derived from patients' tissues and cancer cell lines.
Insights
Heat shock protein 90 (HSP90) inhibitor 17AAG shows anticancer effects in liposarcoma. It reduces tumor growth by inhibiting oncogenic and angiogenic pathways, including AKT and ERK signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Heat shock protein 90 (HSP90) inhibitors are explored for cancer therapy.
- Limited research exists on HSP90 inhibitors' effects on liposarcoma.
- HSP90 inhibitors' anticancer mechanisms involve oncogenic and angiogenic signaling pathways.
Purpose of the Study:
- To investigate the therapeutic effects of the HSP90 inhibitor 17AAG on liposarcoma.
- To evaluate the anti-oncogenic and anti-angiogenic potential of 17AAG in liposarcoma models.
- To analyze the impact of 17AAG on key signaling pathways involved in liposarcoma progression.
Main Methods:
- Liposarcoma cell lines (LPS 246) and patient-derived cells (PDCs) were used.
- Cell viability, migration, and quantitative polymerase chain reaction (qPCR) assays were performed.
- In vivo studies involved a liposarcoma xenograft mouse model with immuno-fluorescence staining.
Main Results:
- 17AAG demonstrated anti-oncogenic and anti-angiogenic effects in liposarcoma cell lines and PDCs.
- 17AAG inhibited protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) activity.
- In vivo, 17AAG treatment reduced tumor size and downregulated VEGFR2, CD31, and STAT3 expression.
Conclusions:
- The HSP90 inhibitor 17AAG effectively targets liposarcoma by disrupting oncogenic and angiogenic signaling.
- 17AAG reduces the activity of AKT, ERK, VEGF, and STAT3 in liposarcoma.
- These findings support the potential of 17AAG as a therapeutic agent for liposarcoma.
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