Abstract
BackgroundDocetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. Transcription factor Forkhead box M1 (FOXM1), which participates in cell proliferation and cell cycle progression, has been reported to affect the sensitivity of chemotherapy. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers.MethodsWe monitored cell growth using MTT and colony formation assays, and cell apoptosis and cell cycle progression using flow cytometry. Wound-healing and transwell assays were used to detect cell invasion and migration. mRNA and protein expression were analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. We monitored FOXM1 binding to the KIF20A promoter using a ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.ResultsFOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, suppressing cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). Exogenous FOXM1 overexpression was found in their parental cells. Specific FOXM1 inhibitor thiostrepton significantly weakened docetaxel resistance in vitro and in vivo. We also found that FOXM1 and KIF20A exhibited consistent and highly correlated overexpression in PCa cells and tissues. FOXM1 also regulated KIF20A expression at the transcriptional level by acting directly on a Forkhead response element (FHRE) in its promoter. KIF20A overexpression could partially reverse the effect on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP) of FOXM1 depletion.ConclusionsOur findings indicate that highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.
Highlights
Docetaxel resistance affects prognosis in advanced prostate cancer (PCa)
Since Forkhead box M1 (FOXM1) and kinesin family member 20 A (KIF20A) are consistently over-expressed in docetaxel-resistant PCa cells and tumor tissues, we explored whether FOXM1 contributed to docetaxel resistance by regulating KIF20A transcription and expression
FOXM1 regulates apoptosis and cell cycle in docetaxel‐treated PCa cells We explored the functional relationship between FOXM1 expression and docetaxel resistance in PCa cells by first evaluating the influence of FOXM1 expression on apoptosis using flow cytometry (FCM)
Summary
Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. This study explores the role of FOXM1 in PCa docetaxel resistance and its association with kinesin family member 20 A (KIF20A), which is known to promote therapeutic resistance in some cancers. Recent studies indicate FOXM1 is commonly overexpressed in many kinds of cancers, including PCa, and its expression is highly correlated with cancer proliferation and metastasis [4,5,6,7,8]. Several studies suggest FOXM1 overexpression confers acquired tolerance to chemotherapy through the regulation of numerous genes, including ATP-binding cassette genes [9, 10], DNA damage repair genes [11], apoptosis-associated genes [12], cancer stem cell-related genes [13, 14]. The function and mechanisms-of-action of expressed FOXM1 during docetaxel resistance in PCa are still largely unknown
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