Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells.

Targeting the phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway is a promising strategy for the treatment of various cancers, including bladder cancer (BC). PF-04691502 is a relatively novel dual PI3K/mTOR inhibitor that exerts inhibitory effects against various cancer cells. However, the effects of PF-04691502 in BC cells have not been clarified thus far. This study aimed to evaluate the antitumour effects of PF-04691502 and the mechanisms underlying these antitumour effects in BC cells. The effects of PF-04691502 on the viabilities of BC cells were examined using the cell counting kit 8 (CCK-8) assay. Cell migration and invasion were measured using the wound healing assay and transwell assay, respectively. Cellular apoptosis was determined using flow cytometry. The change in the cellular protein levels was measured using western blotting. siRNA was used to study the role of PTEN in the antitumour effects of PF-04691502. PF-04691502 inhibited the proliferation, migration, and invasion of BC cells. Additionally, PF-04691502 induced apoptosis of BC cells via the intrinsic pathway. PF-04691502 inhibited the expression of Mcl-1 and the PI3K/Akt/mTOR pathway in BC cells. In addition, PF-04691502 increased the apoptosis induced by various chemotherapeutic agents in BC cells. Taken together, PF-04691502 could be used alone or in combination with other chemotherapeutic agents in the treatment of BC.

Ipatasertib (GDC-0068) and erdafitinib co-treatment for inducing mitochondrial apoptosis through Bim upregulation in bladder cancer cells.

Bladder cancer (BC) is a common malignancy of the urological system that still lacks effective treatment. It is frequently characterised by dysregulation of fibroblast growth factor receptor (FGFR) signalling. FGFR inhibitors have been proven as a promising treatment for BC in clinical settings. Besides the FGFR signalling, the therapeutic effects of FGFR inhibitors are often limited owing to various mechanisms, such as the activation of the Akt signalling pathway. Therefore, this study aimed to examine the synergistic effects of ipatasertib, a FGFR inhibitor, and erdafitinib, an Akt inhibitor, in BC cells. Ipatasertib and erdafitinib co-treatment synergistically inhibited cell proliferation and induced BC cell death. Mechanically, ipatasertib and erdafitinib induced the activation of Bax, an essential protein for cell death. Moreover, erdafitinib, which inhibited the Akt signalling pathway, is responsible for Bim upregulation, a condition critical to achieving the synergistic effects. Therefore, our data suggest that ipatasertib and erdafitinib co-treatment is a promising strategy for BC.

Long non-coding RNA UCA1 contributes to the progression of prostate cancer and regulates proliferation through KLF4-KRT6/13 signaling pathway.

Long non-coding RNAs (lncRNAs) UCA1 have been shown to paly an important regulatory roles in cancer biology, and UCA1 dysfunction is related to TNM stage, metastasis and postoperative survival in several cancers. However, the biological role and clinical significance of UCA1 in the carcinogenesis of prostate cancer (PC) remain largely unclear. Herein, we found that UCA1 was abnormally upregulated in tumor tissues from PC patients, and patients with high UCA1 levels had a significantly poorer prognosis. Intriguingly, the mRNA and protein levels of KLF4 were significantly increased in tumor tissues, which was highly correlated to UCA1 levels. Moreover, UCA1 depletion inhibited the growth and induced apoptosis in PC3 and LNCaP cell lines. In addition, UCA1 loss-of-function could decrease KLF4 expression, subsequently, the downregulation of KRT6 and KRT13. Taken together, our study indicated that UCA1 had a crucial role in the tumorigenesis of PC. Moreover, UCA1 loss-of-function inhibited cell proliferation and induced cell apoptosis, at least partially, through inactivation KLF4-KRT6/13 cascade.