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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Combination effects of arsenic trioxide and fibroblast growth factor receptor inhibitor in squamous cell lung
Sze-Kwan Lam1, Leanne Lee Leung1, Yuan-Yuan Li1
1Division of Respiratory Medicine, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China.
Objectives:
Lung cancer remains the top cancer killer worldwide, with squamous cell carcinoma (SCC) as the second commonest histologic subtype. Arsenic trioxide (ATO) was previously shown to suppress growth of lung cancer. Fibroblast growth factor receptor (FGFR) amplification was recently demonstrated in lung SCC, with specific FGFR inhibitor (e.g. PD173074) developed as a potential targeted therapy. Therefore the combination effects of ATO and PD173074 in SCC was studied.
Materials And Methods:
The combination of ATO/PD173074 was studied in a proof-of-principle model using a lung SCC cell line with FGFR1 overexpression: SK-MES-1. The effects of ATO and/or PD173074 on cell viability and protein expression were studied by MTT assay and Western blot respectively. Cell cycle analysis, phosphatidylserine externalization and mitochondrial membrane depolarization were monitored by flow cytometry. FGFR1 knockdown was performed with siRNAs. Proteasome inhibitor (MG-132) was used to study the degradation mechanism. In vivo effect of ATO and/or PD173074 was investigated using a nude mice xenograft model.
Results:
Combined ATO/PD173074 reduced cell viability along with increased sub-G1 population, phosphatidylserine externalization and mitochondrial membrane depolarization more significantly than single treatments. Downregulation of FGFR1, p-Akt, Akt, p-Src, Src, p-c-Raf, c-Raf, Erk and survivin as well as upregulation of p-Erk and cleaved PARP were observed upon ATO and/or PD treatment. MG-132 partially reversed the degradation of Akt, Src, c-Raf and Erk induced by ATO/PD, suggestive of ubiquitin-independent proteasome-dependent degradation. However, the mechanism of FGFR1 downregulation remained unknown. Downregulation of FGFR1, Akt, Src, c-Raf and Erk as well as cleaved PARP elevation induced by ATO and/or PD were confirmed in vivo.
Conclusion:
Massive protein degradation (FGFR1, Akt, Src, c-Raf and Erk) was induced by ATO and/or PD173074 treatment mainly mediated by activation of proteasomal degradation in SCC cell line SK-MES-1 in vitro and in vivo.
Insights
Arsenic trioxide (ATO) and FGFR inhibitor (PD173074) combination therapy significantly reduced lung squamous cell carcinoma (SCC) cell viability. This treatment induced massive protein degradation via proteasomal pathways, offering a potential targeted therapy for SCC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Squamous cell carcinoma (SCC) is the second most common histological subtype of lung cancer.
- Fibroblast growth factor receptor (FGFR) amplification is implicated in lung SCC, with FGFR inhibitors like PD173074 showing therapeutic potential.
Purpose of the Study:
- To investigate the combined therapeutic effects of Arsenic Trioxide (ATO) and PD173074 in lung squamous cell carcinoma.
- To elucidate the molecular mechanisms underlying the combination therapy's efficacy.
Main Methods:
- Utilized the lung SCC cell line SK-MES-1 with FGFR1 overexpression.
- Assessed cell viability using MTT assays and protein expression via Western blot.
- Analyzed cell cycle, phosphatidylserine externalization, and mitochondrial membrane potential by flow cytometry.
- Investigated protein degradation mechanisms using proteasome inhibitor MG-132.
- Evaluated in vivo efficacy in a nude mice xenograft model.
Main Results:
- Combined ATO/PD173074 significantly reduced cell viability and induced apoptosis-related markers (sub-G1 population, phosphatidylserine externalization, mitochondrial depolarization) compared to single treatments.
- Treatment led to downregulation of FGFR1 and key signaling proteins (Akt, Src, c-Raf, Erk) and upregulation of cleaved PARP.
- Proteasome inhibitor MG-132 partially reversed the degradation of Akt, Src, c-Raf, and Erk, suggesting proteasome-dependent degradation.
- In vivo studies confirmed the downregulation of FGFR1, Akt, Src, c-Raf, Erk, and elevated cleaved PARP.
Conclusions:
- The combination of ATO and PD173074 induces massive protein degradation, primarily through proteasomal pathways, in lung SCC cells.
- This proteasome-mediated degradation of FGFR1, Akt, Src, c-Raf, and Erk is a key mechanism for the observed anti-cancer effects.
- The findings support the potential of combined ATO and PD173074 as a targeted therapy for lung SCC.
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