FOXM1 contributes to docetaxel resistance in castration-resistant prostate cancer by inducing AMPK/mTOR-mediated autophagy

Jia, Lin; Wang, Weiwan; Hu, Tingting; Zhu, Gangjie; Li, Linan; Zhang, Chengyang; Xu, Zheng; Yu, Hongbo; Wu, Hongfei; Zhu, Jun

doi:10.1016/j.canlet.2019.11.014

Cited by 109 publications

(84 citation statements)

References 41 publications

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“…It is well known that KIF20A is abnormally highly expressed in many tumors and has a poor prognosis, including for PCa [16,17,19]. The association between FOXM1 and KIF20A in PCa was therefore investigated, with the protein levels of FOXM1 and KIF20A in DU145, VCaP, and their resistant cells being assessed.…”

Section: Foxm1 and Kif20a Are Consistently Expressed In Pcamentioning

confidence: 99%

“…Some studies indicate KIF20A is transcriptionally regulated by FOXM1 in certain cancer cells, and that their expression is consistently elevated after treatment with paclitaxel. FOXM1 or KIF20A silencing signi cantly improved the chemosensitivity of paclitaxel [16][17]. However, their potential interaction and effect on docetaxel-mediated PCa chemotherapy have yet to be explored.…”

Section: Introductionmentioning

confidence: 99%

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FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

Guo

et al. 2020

Preprint

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Background: Docetaxel resistance affects prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The 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.Methods: We 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 the ChIP assay. Tumorigenicity in nude mice was used to assess in vivo tumorigenicity.Results: FOXM1 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 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.Conclusions: Our findings indicate highly expressed FOXM1 may help promote docetaxel resistance by inducing KIF20A expression, providing insight into novel chemotherapeutic strategies for combatting PCa docetaxel resistance.

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Section: Foxm1 and Kif20a Are Consistently Expressed In Pcamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

Guo

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Moreover, several studies indicated that FOXM1 overexpression conferred acquired chemotherapy tolerance through the regulation of many genes, including ATP-binding cassette genes [9][10], DNA damage repair genes [11], apoptosis-associated genes [12], cancer stem cell-related genes [13][14], and so on. In our previous study, we reported that FOXM1 overexpression can signi cantly reduce the inhibitory effect of docetaxel on cell proliferation in PCa by inducing autophagy [15]. However, the exact biology functions and mechanisms of FOXM1 expression during docetaxel resistance in PCa are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

wang

et al. 2020

Preprint

Self Cite

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Background：Resistance to docetaxel is an important factor which affects the prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), participating in cell cycle progress and cell proliferation, has been reported to affect the sensitivity of chemotherapy. The present study aims to explore the role of FOXM1 in docetaxel resistance of PCa and how FOXM1 is associated with kinesin family member 20 A (KIF20A), which has been demonstrated to promote the development of therapeutic resistance in some cancers. Methods: We monitored cell growth by MTT and colony formation assays , and cell apoptosis and cell cycle through flow cytometry. Wound-healing and transwell assays were performed to detect cell migration and invasion. The mRNA and protein expression of gene were analyzed by by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. We determined the binding of FOXM1 on the KIF20A promoter by the ChIP assay. Tumorigenicity in nude mice was employed to assess tumorigenicity in vivo. Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, and suppressed cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). The opposite trend was found in their parental cells with exogenous FOXM1 overexpression. Furthermore, thiostrepton, a specific inhibitor for FOXM1, significantly attenuated docetaxel resistance in vitro and in vivo. Additionally, we found that FOXM1 and KIF20A were consistently overexpressed and highly correlated in PCa cells and tissues. Further studies demonstrated that FOXM1 regulated the expression of KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Moreover, KIF20A overexpression could partially reverse the effects of FOXM1 depletion on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP). Conclusions: our findings suggest that highly expressed FOXM1 may promote docetaxel resistance partly through the induction of KIF20A expression and provide insights into novel chemotherapeutic strategies for docetaxel resistance in PCa.

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“…Mechanisms of docetaxel resistance are not completely understood. Known mechanisms of resistance to docetaxel include increased expression of multidrug resistance (MDR) genes, tubulin alterations, deregulation of growth factors, and intracellular signaling pathways activation, tumor microenvironment, etc (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer via FGF2/ERG/Akt/mTOR Signaling Pathway

Zhou¹,

Su²,

Han³

et al. 2020

Preprint

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Abstract Background Docetaxel is a first-line chemotherapy for the treatment of patients with castration-resistant prostate cancer (CRPC). Despite the good initial response of docetaxel, drug resistance will inevitably occur. Mechanisms underlying docetaxel resistance are not well elaborated. Endothelial cells (ECs) have been implicated in the progression and metastasis of prostate cancer (PCa). However, little attention has been paid to the role of ECs in the development of docetaxel resistance in PCa. Methods Here, we sought to investigate the function and mechanism of ECs involving in the docetaxel resistance of PCa. The 22Rv1 and C4-2B PCa cell lines were cultured with or without human umbilical vein endothelial cells (HUVEC). The proliferation of each PCa cell line was assessed by CCK8 and EdU assays. Cell viability of each PCa cell line treated with docetaxel was evaluated by CCK8. Apoptosis was measured by flow cytometry. Quantitative reverse transcription (RT)-PCR assay was used to determine the expression of ETS related gene (ERG) in each PCa cell line and FGF2 in HUVEC. The proteins including ERG, Caspase3, PARP, Akt, p-Akt, mTOR and p-mTOR were quantified by western blotting. ERG overexpressing C4-2B cells(C4-2B-ERG) were constructed by transfection with pLenti6.3-ERG lentivirus. C4-2B-ERG cells were knocked down by transfecting with ERG siRNAs. Differentially expressed cytokines between the serum-free media from 22Rv1 and 22Rv1/HUVEC co-culture system were detected by human cytokine array and determined by ELISA assay. Tumors were induced in mice by injecting 22Rv1 cells with or without HUVEC and treated with docetaxel. Tumor growth and apoptosis were examined by immunohistochemistry and TUNEL respectively. Results ECs promoted proliferation and inhibited apoptosis in PCa cells (in vitro) and mouse xenograft tumors induced by these cells (in vivo) under docetaxel treatment. ECs secreted FGF2 to induce ERG expression and activate the Akt/mTOR signaling pathway in PCa cells contributing to docetaxel resistance. Blocking FGF2 could reverse the enhancing effects of HUVEC on docetaxel resistance in PCa cells. Inhibition of the Akt/mTOR signaling pathway could alleviate chemoresistance mediated by ERG. Conclusion ECs promote docetaxel resistance via FGF2/ERG/Akt/mTOR signaling pathway in PCa cells. Targeting FGF/ FGFR signaling may represent a promising therapeutic strategy to overcome docetaxel resistance.

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FOXM1 contributes to docetaxel resistance in castration-resistant prostate cancer by inducing AMPK/mTOR-mediated autophagy

Cited by 109 publications

References 41 publications

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer via FGF2/ERG/Akt/mTOR Signaling Pathway

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