KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy

Jia, Jing; Zhang, Haibao; Shi, Qi; Yang, Chao; Ma, Jianbin; Jin, Bin; Wang, Xinyang; He, Dalin; Guo, Peng

doi:10.7150/thno.33282

Cited by 57 publications

(50 citation statements)

References 37 publications

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“…Autophagy has been reported to decrease the sensitivity of hepatoma cells to chemotherapeutic agents by affecting their apoptotic potential [23]. Evidence has also suggested that autophagy plays critical roles in docetaxel chemoresistance [5]. In present study, we performed studies in PC3 and DU145 cells con rmed that MSCs could signi cantly induce autophagy in CRPC cells (Fig.…”

Section: Discussionsupporting

confidence: 64%

Mesenchymal Stem Cells Desensitize Castration-resistant Prostate Cancer to Docetaxel Chemotherapy via Inducing TGF-β1-mediated Cell Autophagy

Zhang

Yang

et al. 2020

Preprint

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Background: Mesenchymal stem cells (MSCs) have been proved to accelerate prostate cancer (PCa) castration resistance progression. The purpose of this study is to investigate the contribution of MSCs to the development of docetaxel resistance in castration-resistant prostate cancer (CRPC) cells and its potential mechanisms.Methods: The effect of MSCs on CRPC cells resistance to docetaxel was determined using in-vivo and in-vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses.Results: MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel.Conclusions: These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.

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Section: Discussionsupporting

confidence: 64%

Mesenchymal Stem Cells Desensitize Castration-resistant Prostate Cancer to Docetaxel Chemotherapy via Inducing TGF-β1-mediated Cell Autophagy

Zhang

Yang

et al. 2020

Preprint

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“…The procedure was described previously 8 . The following antibodies were used: KLF5 (ab24331), MMP9 (ab38898), and IGF1 (ab9572) (Abcam, Cambridge, UK), p-STAT3 (Tyr705) (#9145), STAT3 (#9139), HDAC1 (#5356), and AR (#5153) (Cell Signaling Technology, Beverly, MA, USA), MMP2 (10373-2-AP) (Proteintech, Rosemont, IL, USA), and β-actin (ComWin Biotech Co. Beijing, China).…”

Section: Western Blotting Analysismentioning

confidence: 99%

“…Krüpple-like transcription factor 5 (KLF5/IKLF/ BTEB2), which is a zinc-finger transcription factor, has various functions in different cellular processes, including proliferation, apoptosis, invasion, and differentiation 4,5 . KLF5 binds specifically to the CA-box and GC-rich regions on target promoters and can recruit other transcription factors and epigenetic enzymes, such as ERβ, SMAD4, p300, and HDAC3, into the transcriptional complex to activate or repress the target gene transcription [6][7][8] . Frequent deletion of the KLF5 gene was reported in human PCa 9 , and protein degradation and promoter DNA methylation also led to KLF5 downregulation in PCa 10 .…”

Section: Introductionmentioning

confidence: 99%

KLF5 inhibits STAT3 activity and tumor metastasis in prostate cancer by suppressing IGF1 transcription cooperatively with HDAC1

Bai

Zhang

et al. 2020

Cell Death Dis

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KLF5 is frequently deleted and downregulated in prostate cancer, and recently it has been reported that KLF5 loss is enriched in the aggressive branches of prostate cancer evolution. However, why KLF5 loss is associated with prostate cancer aggressiveness is still not clear. Herein, we analyzed KLF5 expression in TCGA and GEO database, as well as prostate cancer tissue microarray, and found that KLF5 expression significantly decreased in prostate cancer accompanying with tumor progression; moreover, KLF5 downregulation was associated with shorter survival of patients. Interestingly, we also found that KLF5 expression was obviously lower in prostate cancer metastases than in localized tissues, indicating that KLF5 downregulation is associated with prostate cancer invasion and metastasis. To assess this effect of KLF5, we knocked down KLF5 in prostate cancer cells and found that KLF5 knockdown promoted invasive ability of prostate cancer cells in vitro and in vivo. Moreover, we found that KLF5 downregulation enhanced the expression of IGF1 and STAT3 phosphorylation, while block of IGF1 with antibody decreased the enhancement of STAT3 activity and prostate cancer cell invasive ability by KLF5 knockdown, indicating that KLF5 inhibits prostate cancer invasion through suppressing IGF1/STAT3 pathway. Mechanistically, we found that KLF5 interacted with deacetylase HDAC1 and KLF5 is necessary for the binding of HDAC1 on IGF1 promoter to suppress IGF1 transcription. Taken together, our results indicate that KLF5 could be an important suppressor of prostate cancer invasion and metastasis, because KLF5 could suppress the transcription of IGF1, a tumor cell autocrine cytokine, and its downstream cell signaling to inhibit cell invasive ability, and reveal a novel mechanism for STAT3 activation in prostate cancer. These findings may provide evidence for the precision medicine in prostate cancer.

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“…To further explore the underlying mechanism of BDH2-induced apoptosis and autophagy, we examined the effect of BDH2 on the expression of classic autophagy-related pathways such as AMPK, MAPK/ Erk1/2, and PI3K/Akt/mTOR signalling [21,22]. As shown in Fig.…”

Section: Ros/pi3k/akt/mtor Axis Contributes To Bdh2-induced Apoptosismentioning

confidence: 99%

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

Liu

Feng

et al. 2020

J Exp Clin Cancer Res

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Background: 3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies. Methods: Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays. Results: BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of Akt Ser473 and mTOR Ser2448. Conclusions: Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.

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KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy

Cited by 57 publications

References 37 publications

Mesenchymal Stem Cells Desensitize Castration-resistant Prostate Cancer to Docetaxel Chemotherapy via Inducing TGF-β1-mediated Cell Autophagy

Mesenchymal Stem Cells Desensitize Castration-resistant Prostate Cancer to Docetaxel Chemotherapy via Inducing TGF-β1-mediated Cell Autophagy

KLF5 inhibits STAT3 activity and tumor metastasis in prostate cancer by suppressing IGF1 transcription cooperatively with HDAC1

BDH2 triggers ROS-induced cell death and autophagy by promoting Nrf2 ubiquitination in gastric cancer

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