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Gene expression profiling reveals the genomic changes caused by MLN4924 and the sensitizing effects of NAPEPLD
Jian-Ang Li1, Yefei Rong1, Weilin Mao1
1Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
MLN4924 inhibits the proteolytic degradation of Cullin-Ring E3 ligase (CRL) substrates and exhibits antitumor activity toward various malignancies, including pancreatic cancer. MLN4924 suppresses tumor growth by altering various key regulator proteins; however, its impact on gene expression in tumors remains unknown. In this study, the genomic changes caused by MLN4924 in pancreatic cancer were examined by gene chip analysis and ingenuity pathway analysis. Eleven pathways were significantly altered (5 activated and 6 inhibited), 45 functions were significantly changed (21 activated and 24 inhibited), and the most activated upstream factor was predicted to be TNF. Of 691 differentially expressed genes, NAPEPLD knockdown showed synergism with MLN4924, as determined by real-time quantitative PCR and high content screening. NAPEPLD knockdown enhanced the effect of MLN4924 on inhibiting proliferation and inducing apoptosis in vitro. In a pancreatic cancer nude mouse model, MLN4924 inhibited tumor growth more significantly in the NAPEPLD knockdown group than in the control group. NAPEPLD expression was higher in pancreatic cancer tissues than in the normal pancreas but was not associated with prognosis. These findings indicate that MLN4924 causes extensive genomic changes in pancreatic cancer cells, and targeting NAPEPLD may increase the efficacy of MLN4924.
Insights
MLN4924 impacts gene expression in pancreatic cancer, revealing new therapeutic targets. Targeting NAPEPLD enhances MLN4924
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- MLN4924 inhibits Cullin-Ring E3 ligase (CRL) substrates, showing antitumor effects in pancreatic cancer.
- The impact of MLN4924 on pancreatic tumor gene expression was previously unknown.
Purpose of the Study:
- To investigate the genomic alterations induced by MLN4924 in pancreatic cancer.
- To identify potential synergistic targets for enhancing MLN4924 efficacy.
Main Methods:
- Gene chip analysis and Ingenuity Pathway Analysis (IPA) were used to examine genomic changes.
- Real-time quantitative PCR and high-content screening assessed the role of NAPEPLD.
- In vitro and in vivo (nude mouse model) experiments evaluated combined MLN4924 and NAPEPLD knockdown effects.
Main Results:
- MLN4924 significantly altered 11 pathways (5 activated, 6 inhibited) and 45 functions (21 activated, 24 inhibited).
- Tumor necrosis factor (TNF) was predicted as the most activated upstream factor.
- NAPEPLD knockdown synergized with MLN4924, enhancing anti-proliferation and pro-apoptosis effects.
- MLN4924 demonstrated more significant tumor growth inhibition in NAPEPLD knockdown mice.
- NAPEPLD expression was elevated in pancreatic cancer tissues but not linked to prognosis.
Conclusions:
- MLN4924 induces widespread genomic changes in pancreatic cancer.
- Targeting NAPEPLD represents a promising strategy to potentiate MLN4924's therapeutic efficacy in pancreatic cancer.
