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FOXM1 mediates resistance to docetaxel in gastric cancer via up-regulating Stathmin.

Li X, Yao R, Yue L, Qiu W, Qi W, Liu S, Yao Y, Liang J - J. Cell. Mol. Med. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology of the Affiliated Hospital of Medical College Qingdao University, Qingdao, China.

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Elevated levels of forkhead box protein M1 (FOXM1) correlate with resistance to docetaxel in gastric cancer. (A, Top) The expression of FOXM1 in three gastric cancer cell lines: AGS, SGC-7901 and MKN-28, shown by western blot. (Bottom) The expression of FOXM1 after transfected with pcDNA3. 1, pcDNA3. 1-FOXM1, non-specific siRNA or FOXM1-siRNA in gastric cell lines AGS, analysed by western blot 48 hrs later. (B) AGS, SGC-7901 and MKN-28 cells were treated with 0.02 mg/l of docetaxel for 0, 24, 48 and 72 hrs. MTT assay was performed to test the cell viability. (C) Gastric cell lines AGS were treated with docetaxel at the concentration of 0.02 mg/l after FOXM1-siRNA or pcDNA3, 1-FOXM1 transfection for 72 hrs. Cell growth curves were drawn by MTT assays. The IC50 in FOXM1 knockdown, overexpressed, non-specific siRNA and pcDNA3, 1 transfected groups was 0.012, 0.040, 0.024 and 0.027 mg/l respectively (D). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 significant.
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fig01: Elevated levels of forkhead box protein M1 (FOXM1) correlate with resistance to docetaxel in gastric cancer. (A, Top) The expression of FOXM1 in three gastric cancer cell lines: AGS, SGC-7901 and MKN-28, shown by western blot. (Bottom) The expression of FOXM1 after transfected with pcDNA3. 1, pcDNA3. 1-FOXM1, non-specific siRNA or FOXM1-siRNA in gastric cell lines AGS, analysed by western blot 48 hrs later. (B) AGS, SGC-7901 and MKN-28 cells were treated with 0.02 mg/l of docetaxel for 0, 24, 48 and 72 hrs. MTT assay was performed to test the cell viability. (C) Gastric cell lines AGS were treated with docetaxel at the concentration of 0.02 mg/l after FOXM1-siRNA or pcDNA3, 1-FOXM1 transfection for 72 hrs. Cell growth curves were drawn by MTT assays. The IC50 in FOXM1 knockdown, overexpressed, non-specific siRNA and pcDNA3, 1 transfected groups was 0.012, 0.040, 0.024 and 0.027 mg/l respectively (D). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 significant.

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.


FOXM1 mediates resistance to docetaxel in gastric cancer via up-regulating Stathmin.

Li X, Yao R, Yue L, Qiu W, Qi W, Liu S, Yao Y, Liang J - J. Cell. Mol. Med. (2014)

Elevated levels of forkhead box protein M1 (FOXM1) correlate with resistance to docetaxel in gastric cancer. (A, Top) The expression of FOXM1 in three gastric cancer cell lines: AGS, SGC-7901 and MKN-28, shown by western blot. (Bottom) The expression of FOXM1 after transfected with pcDNA3. 1, pcDNA3. 1-FOXM1, non-specific siRNA or FOXM1-siRNA in gastric cell lines AGS, analysed by western blot 48 hrs later. (B) AGS, SGC-7901 and MKN-28 cells were treated with 0.02 mg/l of docetaxel for 0, 24, 48 and 72 hrs. MTT assay was performed to test the cell viability. (C) Gastric cell lines AGS were treated with docetaxel at the concentration of 0.02 mg/l after FOXM1-siRNA or pcDNA3, 1-FOXM1 transfection for 72 hrs. Cell growth curves were drawn by MTT assays. The IC50 in FOXM1 knockdown, overexpressed, non-specific siRNA and pcDNA3, 1 transfected groups was 0.012, 0.040, 0.024 and 0.027 mg/l respectively (D). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 significant.
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fig01: Elevated levels of forkhead box protein M1 (FOXM1) correlate with resistance to docetaxel in gastric cancer. (A, Top) The expression of FOXM1 in three gastric cancer cell lines: AGS, SGC-7901 and MKN-28, shown by western blot. (Bottom) The expression of FOXM1 after transfected with pcDNA3. 1, pcDNA3. 1-FOXM1, non-specific siRNA or FOXM1-siRNA in gastric cell lines AGS, analysed by western blot 48 hrs later. (B) AGS, SGC-7901 and MKN-28 cells were treated with 0.02 mg/l of docetaxel for 0, 24, 48 and 72 hrs. MTT assay was performed to test the cell viability. (C) Gastric cell lines AGS were treated with docetaxel at the concentration of 0.02 mg/l after FOXM1-siRNA or pcDNA3, 1-FOXM1 transfection for 72 hrs. Cell growth curves were drawn by MTT assays. The IC50 in FOXM1 knockdown, overexpressed, non-specific siRNA and pcDNA3, 1 transfected groups was 0.012, 0.040, 0.024 and 0.027 mg/l respectively (D). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001 significant.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology of the Affiliated Hospital of Medical College Qingdao University, Qingdao, China.

Show MeSH
Related in: MedlinePlus