Increased chemoresistance to paclitaxel in the MCF10AT series of human breast epithelial cancer cells
| Autor: | Soo-Jeong Lim, So Hee Kim, Hyeon Gyeom Choi, Chae Kyung Jeon |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Cancer Research Pathology medicine.medical_specialty Paclitaxel Cell Apoptosis Breast Neoplasms DNA Fragmentation Biology medicine.disease_cause chemistry.chemical_compound Cell Line Tumor medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Cell Proliferation Cell growth Akt/PKB signaling pathway G1 Phase Epithelial Cells General Medicine Cell cycle Neoplasm Proteins medicine.anatomical_structure Oncology chemistry Cell culture Drug Resistance Neoplasm Cancer research ATP-Binding Cassette Transporters Female Tumor Suppressor Protein p53 Carcinogenesis Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Oncology reports. 33(4) |
| ISSN: | 1791-2431 |
| Popis: | The MCF10AT cell series of human breast epithelial cancer cells includes normal MCF10A (10A), premalignant MCF10AT (10AT) and MCF10ATG3B (10ATG3B), and fully malignant MCF10CA1a (10CA1a) cells. The series is a unique model system showing progressive tumorigenic potential with the same origin. The effects of paclitaxel, a microtubule inhibitor, were evaluated in this cell system. Paclitaxel inhibited cell proliferation in a time-dependent (24, 48 and 72 h) and concentration-dependent (0-10 nM) manners with less sensitivity in 10CA1a cells. Treatment with paclitaxel (10 nM) for 24 h induced apoptosis in 10A, 10AT, 10ATG3B and 10CA1a cells, with 23.6, 26.1, 25.2 and 8.96%, respectively, in the sub-G1 phase. Treatment with paclitaxel (0-10 nM) for 24 h, resulted in the appearance of DNA fragmentation (a hallmark of apoptosis) with less sensitivity in the 10CA1a tumor cells. Paclitaxel increased p53 protein expression in 10A, 10AT, 10ATG3B and 10CA1a cells, by 87, 102, 812 and 84%, respectively. The p21Waf1/Cip1 protein expression increased by 2.57-, 1.53- and 2.48-fold in 10A, 10AT and 10ATG3B cells, respectively, with negligible detection in the 10CA1a cells. Activation of the Akt signaling pathway was observed in the MCF10AT cell lineage and the protein expression of phospho-Akt (Ser473 and Thr308). The downstream targets of this pathway, phospho-p70S6K and phospho-S6RP, were also inhibited by paclitaxel in 10A, 10AT and 10ATG3B cells, but minimally inhibited in 10CA1a cells, suggestive of chemoresistance in 10CA1a cells. The effects of paclitaxel on the multidrug resistance 1 (MDR1), MRP1 and breast cancer resistance protein (BCRP) gene expression were not significant in the MCF10AT cell lineage. These results collectively indicated that paclitaxel inhibited cell proliferation and induced apoptosis in the MCF10AT cell lineage, with chemoresistance in 10CA1a tumor cells. The decreased responsiveness to paclitaxel observed in 10CA1a tumor cells was likely due, in part, to activation of the Akt signaling pathway and a high expression of wild-type p53 with lack of p21Waf1/Cip1. |
| Databáze: | OpenAIRE |
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