Abstract
Objective The aim of the present study was to investigate the effect of forkhead box M1 (FOXM1) to paclitaxel resistance in cervical cancer cells, to determine the underlying mechanism, and to identify novel targets for the treatment of paclitaxel-resistant cervical cancer. Methods Paclitaxel-resistant Caski cells (Caski/Taxol cells) were established by intermittently exposing the Caski cells to gradually increasing concentrations of paclitaxel. The association between FOXM1, ATP-binding cassette subfamily C member 5 (ABCC5), and cervical cancer cell drug resistance was assessed by overexpressing or knocking down the expression of FOXM1 in Caski or Caski/Taxol cells. The protein and mRNA expression levels, the ratio of cellular apoptosis, and cell migration as well as intracellular drug concentrations were measured in cells following the different treatments. Results After the successful establishment of resistant Caski/Taxol cells, cell cycle distribution analysis showed that a significantly larger percentage of Caski/Taxol cells was in the G0/G1 stage compared with the Caski cells (P < 0.01), whereas a significantly larger percentage of Caski cells was in the S and G2/M stage compared with the Caski/Taxol cells following treatment with paclitaxel (P < 0.01). Both the protein and mRNA expression levels of FOXM1 and ABCC5 transporters were significantly higher in the paclitaxel-resistant Caski/Taxol cells compared with Caski cells (P < 0.05). Knockdown of FOXM1 significantly lowered the protein expression levels of FOXM1 and ABCC5. Intracellular paclitaxel concentrations were significantly higher amongst the Caski/Taxol cells following the knockdown of FOXM1 by shRNA or Siomycin A (P < 0.05). Conclusion FOXM1 promotes drug resistance in cervical cancer cells by regulating ABCC5 gene transcription. The knockdown of FOXM1 with shRNA or Siomycin A promotes paclitaxel-induced cell death by regulating ABCC5 gene transcription.
Highlights
Paclitaxel was approved by the US Food and Drug Administration for the treatment of ovarian cancer in 1992 and has since become a first-line treatment option for numerous types of cancer [1,2,3]
The results showed that intracellular paclitaxel concentrations were significantly increased following forkhead box M1 (FOXM1) knockdown by shRNA or inhibition by Siomycin A, indicating the potential of Siomycin A to sensitize chemo-resistant cancer cells to paclitaxel. ∗∗∗ P < 0:001
Paclitaxel (50, 100, 150, 200, and 250 μM) significantly reduced the viability of Caski cells compared with the Caski/Taxol cells 48 h after treatment (Figures 1(a) and 1(b))
Summary
Paclitaxel was approved by the US Food and Drug Administration for the treatment of ovarian cancer in 1992 and has since become a first-line treatment option for numerous types of cancer [1,2,3]. The primary target of paclitaxel is the intracellular microtubule system. By promoting microtubule polymerization and inhibiting microtubule depolymerization, paclitaxel can arrest cells in the G2/M phase, eventually resulting in cell death. During the initial treatment stages, most patients with cervical cancer show adequate sensitivity to chemotherapeutic drugs. Following short-term treatment, acquired drug resistance may develop and result in failure of chemotherapy [4,5,6].
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