No abstract

Our findings provide the first demonstration of the anticancer effect of TQ on bladder cancer, and the relationship between ER stress and mitochondrial dysfunction was clearly understood when the apoptosis progressed is revealed.

KLF5 is frequently deleted or downregulated in prostate cancer. However, it is not known whether downregulation of KLF5 is associated with the response of prostate cancer cells to chemotherapy and/or prognosis of patients.Methods: We monitored cell growth by MTT and colony formation assays, and cell autophagy through tandem fluorescence microscopy and transmission electron microscopy. Gene expression was analyzed by RT-qPCR and Western blotting. We determined the binding of KLF5 together with HDAC3 on the beclin-1 (BECN1) promoter by the ChIP assay, oligonucleotides pulldown, and co-immunoprecipitation. The effect of docetaxel on cell growth in vivo was examined in a CWR22RV1 xenograft tumor mouse model.Results: In the present study, we found that KLF5 down-regulation was associated with progression of prostate cancer and poor prognosis of patients. KLF5 knockdown reduced the sensitivity of prostate cancer cells to docetaxel in vitro and in vivo, and docetaxel treatment decreased the expression of KLF5. Moreover, we confirmed that docetaxel treatment inhibited cell death by inducing autophagy in prostate cancer cells. Thus, we hypothesized that KLF5 could be a regulator of cell autophagy. Interestingly, KLF5 could inhibit prostate cancer cell autophagy by suppressing the transcription of BECN1 cooperatively with HDAC3. Another significant finding was that docetaxel treatment repressed KLF5 expression through AMPK/mTOR/p70S6K signaling pathway resulting in increased BECN1, induction of cell autophagy, and promotion of cell survival in castration-resistant prostate cancer cells.Conclusions: Our results indicated that downregulation of KLF5 promoted cell autophagy in prostate cancer. Furthermore, reduced KLF5 also facilitated cell autophagy induced by docetaxel resulting in desensitization to the drug and cell survival. Decreased levels of KLF5 led to increased BECN1 via AMPK/mTOR/p70S6K signaling. Thus, repression of BECN1 and cell autophagy was critical for KLF5 to increase the sensitivity of prostate cancer cells to docetaxel.

Aim JQ1, a BET bromodomain inhibitor, is a promising therapeutic approach for bladder cancer (BC). Our study aimed to determine whether autophagy is induced by JQ1 and its potential role toward proliferation in BC. Methods Cell proliferation was determined by methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay, cell counting assay, and colony formation assay. Autophagosomes and autolysosomes were observed by transmission electron microscopy and mRFP‐EGFP‐LC3 fluorescence assay. 3‐MA, BAFA1, NH 4 Cl, and siATG5 were used to inhibit autophagy. AMPK siRNA was used to knock down AMPK. T24 xenograft model in mice was chosen to perform in vivo studies. Autophagy markers LC‐3B and p62, p‐AMPK α , p‐ACC, p‐ULK1, p‐mTOR and p‐LKB1 were determined by western blot in vitro studies and by immunohistochemistry (IHC) in vivo specimens. Results We found that BC cell proliferation was suppressed by JQ1; moreover, JQ1 induced the accumulation of autophagosomes and autolysosomes, and autophagy flux, and the growth suppression capacity of JQ1 was attenuated by autophagy inhibitors. Furthermore, we found that JQ1 induced the phosphorylation of AMPK α , and AMPK α knockdown attenuated autophagy induction and anti‐proliferation effect induced by JQ1 in BC cells, indicating that autophagy induced by JQ1 is dependent on AMPK α . Through endogenous immunoprecipitation analysis, we found that JQ1 dramatically increased the interaction between LKB1 and AMPK α , which may lead to more AMPK activation. Proliferation inhibition, autophagy induction, and LKB1/AMPK activation capacities of JQ1 were further confirmed in vivo. Conclusions Taken together, our results demonstrate that autophagy is induced by JQ1 through activation of LKB1/AMPK pathway, and the autophagy induced by JQ1 positively contributes to the inhibition of BC cell proliferation. These findings provide a novel point of view to understand the mechanism of how targeting BET bromodomain suppress cancer cell growth and suggest that targeting BET bromodomain might be a potential approach to treat BC in the future.

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.