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Published on: January 11, 2019
Transcriptome analysis of an AKT inhibitor-resistant endometrial cancer cell line
Takafumi Onishi1,2, Tsuyoshi Takashima3, Kazuki Shibahara4,5
1Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, 34 Yamada-cho, Oyake, Yamashina-ku, Kyoto, 607-8175, Japan. onishi-ta@tachibana-u.ac.jp.
Background:
Drug resistance in endometrial cancer (EC) is a serious problem and a barrier to improving prognosis. The PI3K/AKT/mTOR pathway is highly activated in EC and can serve as a potential therapeutic target. Inhibitors against AKT have been developed, but resistance to these inhibitors is a concern. This study aimed to establish AKT inhibitor resistant cell lines and identify differentially expressed genes (DEGs) between parental and AKT inhibitor resistant cell lines to understand the mechanism of drug resistance to AKT inhibitors in EC.
Methods:
The sensitivity of eight EC cell lines to AKT inhibitor was analyzed. One of them was used to establish a drug-resistant cell line. DEGs were examined using RNA sequencing (RNA-seq). Furthermore, DEGs were comprehensively analyzed to identify hub genes. Hub genes were evaluated using quantitative real-time polymerase chain reaction.
Results:
RNA-seq identified 617 DEGs. Hub genes were selected using bioinformatics analysis. The top 10 hub genes were TNF, CDH1, CCND1, COL1A1, CDH2, ICAM1, CAV1, THBS1, NCAM1, and CDKN2A. Relative mRNA expression was significantly upregulated for TNF, CDH1, CCND1, THBS1, p16INK4a, and p14ARF and significantly downregulated for CDH2, ICAM1, and NCAM1 in borussertib-resistant EC cell line.
Conclusions:
Drug resistance to AKT inhibitors may depend on genes related to cell adhesion-mediated resistance and transforming growth factor β signaling.
Insights
Drug resistance in endometrial cancer (EC) hinders treatment. This study identified key genes involved in resistance to AKT inhibitors, revealing potential mechanisms for overcoming this challenge in EC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Endometrial cancer (EC) drug resistance is a significant clinical challenge.
- The PI3K/AKT/mTOR pathway is frequently activated in EC and is a therapeutic target.
- Resistance to AKT inhibitors is a growing concern in EC treatment.
Purpose of the Study:
- To establish AKT inhibitor-resistant endometrial cancer cell lines.
- To identify differentially expressed genes (DEGs) associated with AKT inhibitor resistance.
- To elucidate the molecular mechanisms underlying drug resistance in EC.
Main Methods:
- Sensitivity analysis of eight EC cell lines to an AKT inhibitor.
- Establishment of an AKT inhibitor-resistant EC cell line.
- RNA sequencing (RNA-seq) to identify DEGs and hub genes, validated by quantitative real-time polymerase chain reaction.
Main Results:
- RNA-seq identified 617 DEGs between parental and resistant EC cells.
- Top 10 hub genes included TNF, CDH1, CCND1, and CDKN2A.
- Significant differential mRNA expression of genes related to cell adhesion and signaling pathways was observed in resistant cells.
Conclusions:
- Drug resistance to AKT inhibitors in EC may involve cell adhesion-mediated resistance.
- Transforming growth factor β signaling pathways may play a role in AKT inhibitor resistance.
- Understanding these mechanisms can inform future therapeutic strategies for resistant EC.
