Paclitaxel resistance in MCF-7/PTX cells is reversed by paeonol through suppression of the SET/phosphatidylinositol 3-kinase/Akt pathway

Abstract

Breast cancer is one of the most prevalent types of malignant tumor. Paclitaxel is widely used in the treatment of breast cancer; however, the major problem contributing to the failure of chemotherapy in breast cancer is the development of drug resistance. Therefore, it is necessary to identify novel therapeutic targets and reversal agents for breast cancer. In the present study, the protein expression levels of SET, protein phosphatase 2A (PP2A) and phosphatidylinositol 3-kinase (PI3K)/Akt pathway were determined in MCF-7/PTX human breast carcinoma paclitaxel-resistant cells using western blot analysis. Small interference RNAs (siRNAs) were used to knock down the gene expression of SET in MCF-7/PTX cells and the cell viability was assessed following treatment with paclitaxel, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays and flow cytometry. In addition, western blot analysis was used to determined PI3K/Akt pathway activity following SET knockdown. Furthermore, the reversal effects of paeonol on paclitaxel, and its underlying mechanisms of action, were investigated using western blot analysis and reverse transcription-quantitative polymerase chain reaction. The results demonstrated that increased levels of SET and PI3K/Akt pathway proteins were present in the MCF-7/PTX cells, compared with normal MCF-7 cells. Knockdown of SET significantly sensitized MCF-7/PTX cells to paclitaxel and induced cell apoptosis. In addition, the expression levels of the adenosine triphosphate binding cassette (ABC) transporter proteins were significantly reduced in the MCF-7/PTX cells compared with the normal MCF-7 cells. SET-induced paclitaxel resistance was found to be associated with the activation of the PI3K/Akt pathway. Paeonol significantly reduced the mRNA and protein expression levels of SET in the MCF-7/PTX cells. Furthermore, paeonol significantly sensitized the MCF-7/PTX to paclitaxel via regulation of ABC transporters, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein. In addition, paeonol inhibited SET-mediated paclitaxel resistance by attenuating PI3K/Akt pathway activity in the MCF-7/PTX cells. In conclusion, the results of the present study demonstrated that SET was associated with paclitaxel resistance in MCF-7/PTX cells, and that paeonol reversed paclitaxel resistance in MCF-7/PTX cells by downregulating the activity of the SET/PP2A/Akt pathway.

SB-T-121205, a next-generation taxane, enhances apoptosis and inhibits migration/invasion in MCF-7/PTX cells

“…Knockdown of transgelin 2 via small interfering RNA sensitized MCF-7/PTX cells to paclitaxel, and suppressed their migration/invasion abilities, suggesting that transgelin 2 might be a new biomarker for breast cancer (16). On the other hand, aberrant activation of the phosphatidylinositol 3 kinase/serine-threonine kinase (PI3K/Akt) pathway contributes to chemo-resistance, tumor metastasis and poor prognosis (17,18). Notably, we reported that the PI3K/Akt pathway was activated in MCF-7/PTX cells and the TAGLN2 -knockdown inhibited the PI3K/Akt pathway, suggesting that the PI3K/Akt pathway would be critical to breast cancer progression (19).…”

Antagonizing SET Augments the Effects of Radiation Therapy in Hepatocellular Carcinoma through Reactivation of PP2A-Mediated Akt Downregulation

“…Using a full panel of HCC cell lines, we showed that the numbers of cancer cell colonies and tumor spheres were significantly reduced by SET knockdown; in contrast, overexpression of SET promoted the growth of HCC. More interestingly, our group and others have found that the activity of SET is associated with the development of resistance to standard anticancer drugs, namely chemotherapies or target therapies, in various malignant diseases (Agarwal et al, 2014;Cristobal et al, 2015;Hung et al, 2015Hung et al, , 2016Zhang et al, 2015). For example, ectopic expression of SET diminished the effects of paclitaxel against non-small cell lung cancer (Hung et al, 2015) and oxaliplatin against colon cancer (Cristobal et al, 2015).…”

The role of SET/I2PP2A in canine mammary tumors

“…4). Because SET KD has been reported to decrease the protein levels of c-Myc and the phosphorylation levels of Akt in human breast cancer cells 16, 22 , we first examined the effects of SET KD on these signaling molecules in CIP-m cells (Fig. 4A,B).…”