Transcriptome analysis of an AKT inhibitor-resistant endometrial cancer cell line.

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 ß signaling.

Immunohistochemical staining of versican as a potential marker for predicting lymph node metastasis in gastric cancer.

Gastric cancer is one of the most common cancers and has a high mortality rate. Lymph node metastasis is a key determinant of prognosis, and an essential mechanism involved in metastasis is the epithelial-mesenchymal transition. In this study, we aimed to assess the diagnostic role of versican (VCAN), a molecule participating in the epithelial-mesenchymal transition, on the detection of metastatic cancer. The expression of VCAN was evaluated using immunohistochemistry, and its biological activity was examined using gastric cancer cell lines. In patients with lymph node metastasis, VCAN expression was more prominent at primary tumor sites. In addition, VCAN was found to promote cell migration in vitro, thus potentially facilitating the distribution of metastases. Overall, increased expression of VCAN at the primary site may signify the development of metastases in lymph nodes because this protein is recognized as contributing to the migration of cancer cells into lymph nodes.

Acquired AKT-inhibitor Resistance Is Mediated by ATP-binding Cassette Transporters in Endometrial Carcinoma.

BACKGROUND/AIM: Endometrial cancer is increasing in prevalence worldwide. It is treated with chemotherapy and radiotherapy, in addition to surgery, but the presence of treatment-resistant tumor cells remains a barrier to effective tumor control. The purpose of this study was to develop drug-resistant cell lines using triciribine, an AKT inhibitor, and investigate the mechanism of acquired resistance. MATERIALS AND METHODS: Triciribine sensitivity assays were performed using Cell Counting Kit-8 (CCK-8) on eight endometrial cancer cell lines. The chosen cell lines were highly sensitive to chemotherapy and radiotherapy. A new triciribine-resistant cell line was established and found to be highly resistant to chemotherapy. Properties of the resistant cell line were identified using molecular and cell biological techniques including CCK-8 and quantitative PCR analysis. RESULTS: HEC-151 had the highest triciribine sensitivity (IC50 value of 0.7±0.1 µM) of the endometrial cancer cell lines tested. We established a triciribine-resistant cell line from HEC-151 by growing cells in the presence of increasing concentrations of triciribine up to 66.6 µM. The resistant HEC-151 cells changed to spindle-shaped morphology and importantly reduced triciribine sensitivity compared to the parental cell line. ABC transporters involved in drug efflux had significantly higher expression levels in ABCB1 (1.4±0.10 times higher), ABCC1 (11.4±0.22 times higher), and ABCC4 (4.5±0.42 times higher). CONCLUSION: In this study, we established a triciribine-resistant cell line from HEC-151 cells. Our data suggest that the mechanism of drug resistance in endometrial cancer cells is attributed to the increased expression of ABC transporters.