FOXM1 mediates resistance to docetaxel in gastric cancer via up-regulating Stathmin.
Bottom Line: It altered microtubule dynamics to protect tumour cells from docetaxel-induced apoptosis.Moreover, when we attenuated FOXM1 expression with FOXM1 inhibitor thiostrepton, docetaxel resistance in gastric cancers was found to be reversed, simultaneously with the down-regulation of FOXM1 and Stathmin.Therefore, FOXM1 can be a useful marker for predicting and monitoring docetaxel response.
Affiliation: Department of Oncology of the Affiliated Hospital of Medical College Qingdao University, Qingdao, China.Show MeSH
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Mentions: We initiated our study by investigating whether there is an association between the expression of FOXM1 and chemotherapy response to docetaxel. To explore it, the human malignant gastric cell lines SGC-7901, AGS and MKN-28, which has different expression levels of FOXM1 (Fig. 1A), were treated with 0.02 mg/l of docetaxel for 72 hrs. With the detection of MTT assay, only 15–20% of the MKN-28 cells survived after treatment, whereas the survival in FOXM1-overexpressed cells was greater than 40% (P < 0.001, Fig. 1B), indicating that the expression of FOXM1 correlated with docetaxel therapeutic efficacy significantly. To further confirm this result, we then transfected pcDNA3.1-FOXM1 and FOXM1-siRNA into AGS cell lines (Fig. 1A) and incubated them at the same drug concentration for 3 days. As shown by cell growth curve, the cell viability was absolutely lower in samples with FOXM1 knockdown, whereas the pcDNA3.1-FOXM1–transfected cells had higher viable rate (P < 0.01, Fig. 1C). Moreover, the hypothesis that knockdown of FOXM1 in AGS sensitized the cells to docetaxel treatment was also demonstrated by IC50 calculations, 0.040 mg/l (pcDNA3.1-FOXM1), 0.027 mg/l (pcDNA3.1) and 0.024 mg/l (non-specific siRNA) versus 0.012 mg/l (siRNA FOXM1; Fig. 1D). These data indicated that FOXM1 can protect cells from docetaxol-induced cell damage.
Affiliation: Department of Oncology of the Affiliated Hospital of Medical College Qingdao University, Qingdao, China.