Lanthanum Chloride Sensitizes Cisplatin Resistance of Ovarian Cancer Cells via PI3K/Akt Pathway.
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ABSTRACT:
SUBMITTER: Fang S
PROVIDER: S-EPMC8714849 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung cancer is the leading cause of cancer death worldwide. Cisplatin is the major DNA-damaging anticancer drug that cross-links the DNA in cancer cells, but many patients inevitably develop resistance with treatment. Identification of a cisplatin sensitizer might postpone or even reverse the development of cisplatin resistance. Halofuginone (HF), a natural small molecule isolated from Dichroa febrifuga, has been found to play an antitumor role. In this study, we found that HF inhibited the proliferation, induced G0/G1 phase arrest, and promoted apoptosis in lung cancer cells in a dose-dependent manner. To explore the underlying mechanism of this antitumor effect of halofuginone, we performed RNA sequencing to profile transcriptomes of NSCLC cells treated with or without halofuginone. Gene expression profiling and KEGG analysis indicated that PI3K/AKT and MAPK signaling pathways were top-ranked pathways affected by halofuginone. Moreover, combination of cisplatin and HF revealed that HF could sensitize the cisplatin-resistant patient-derived lung cancer organoids and lung cancer cells to cisplatin treatment. Taken together, this study identified HF as a cisplatin sensitizer and a dual pathway inhibitor, which might provide a new strategy to improve prognosis of patients with cisplatin-resistant lung cancer.
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Project description:Cisplatin resistance is a challenge in the treatment of epithelial ovarian cancer. Here, clinical data showed that the level of netrin-G1 (NTNG1) in cisplatin-resistant cancer was higher than that in cisplatin-sensitive cancer (2.2-fold, p = 0.005); patients with a high NTNG1 level in cancer tissues had shorter progression-free survival (11.0 vs. 25.0 months, p = 0.010) and platinum-free interval (5.0 vs. 20.0 months, p = 0.021) compared with patients with a low level. Category- or stage-adjusted analyses demonstrated that the association between the NTNG1 level and prognosis occurred in type II or FIGO III/IV cancer. The basal level of NTNG1 in SKOV3/DDP cells (a cisplatin-resistant subline) was higher than that in SKOV3 cells; therefore, NTNG1 was overexpressed in SKOV3 cells, or silenced in SKOV3/DDP cells. Knocking in NTNG1 reduced the action of cisplatin to decrease cell death and apoptosis of SKOV3 cells, accompanied by upregulation of p-AXL, p-Akt and RAD51; however, opposite effects were observed in SKOV3/DDP cells after knocking down NTNG1. Co-immunoprecipitation demonstrated that NTNG1 bound GAS6/AXL. Silencing NTNG1 enhanced cisplatin effects in vivo, decreasing tumor volume/mass. These data suggested that a high NTNG1 level can result in cisplatin resistance in ovarian cancer cells via the GAS6/AXL/Akt pathway and that NTNG1 may be a useful target to overcome resistance.
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Project description:The aim of the study was to explore the possible mechanisms that Guizhi Fuling Wan (GFW) enhances the sensitivity of the SKOV3/DDP ovarian cancer cells and the resistant xenograft tumours to cisplatin. Rat medicated sera containing GFW were prepared by administering GFW to rats, and the primary bioactive constituents of the sera were gallic acid, paeonol, and paeoniflorin analysed by HPLC/QqQ MS. Cell counting kit-8 analysis was shown that coincubation of the sera with cisplatin/paclitaxel enhanced significantly the cytotoxic effect of cisplatin or paclitaxel in SKOV3/DDP cells. The presence of the rat medicated sera containing GFW resulted in an increase in rhodamine 123 accumulation by flow cytometric assays and a decrease in the protein levels of P-gp, phosphorylation of AKT at Ser473, and mTOR in a dose-dependent manner in SKOV3/DDP cells by western blot analysis, but the sera had no effect on the protein levels of PI3K p110? and total AKT. The low dose of GFW enhanced the anticancer efficacy of cisplatin and paclitaxel treatment in resistant SKOV3/DDP xenograft tumours. GFW could sensitize cisplatin-resistant SKOV3/DDP cells by inhibiting the protein level and function of P-gp, which may be medicated through inactivation of the PI3K/AKT/mTOR pathway.
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Project description:Background:Esophageal squamous cell carcinoma (ESCC) is the eighth most common cancer worldwide and is one of the most lethal malignancies. Cisplatin (DDP) is a key drug for ESCC treatment, but the presence of chemotherapy resistance limits the use of DDP. To enhance chemosensitivity to DDP is important for ESCC treatment. Methods:qRT-PCR and Western blotting detected mRNA and protein expression in ESCC tissues and cells. Luciferase reporter assay assessed the interaction between miR-145 and AKT3. Cell cycle, apoptosis and proliferation were investigated with flow cytometry and MTT assay, respectively. Nude mice xenograft model was established, and immunohistochemistry (IHC) and TUNEL assay were conducted to detect Ki-67 level and apoptosis in xenograft tumor. Results:Down-regulated miR-145 and up-regulated AKT3 were observed in ESCC tissues and cells. Luciferase reporter assay revealed that miR-145 negatively regulated AKT3 through binding to its 3'-UTR. Overexpression of miR-145 or knockdown of AKT3 promoted DDP-induced cell cycle arrest and apoptosis, as well as reduced IC50 of DDP treatment, which was reversed by AKT3 overexpression. The expression level of MRP1, P-gp, CyclinD1, c-Myc and anti-apoptotic protein Bcl-2 were down-regulated, while pro-apoptotic protein Bax was up-regulated by miR-145. Furthermore, overexpression of miR-145 enhanced the DDP-induced tumor growth suppression in vivo. Conclusion:miR-145 increased the sensitivity of ESCC to DDP, and facilitated DDP-induced apoptosis, cycle arrest by directly inhibiting PI3K/AKT signaling pathway to decrease multidrug resistance-associated proteins MRP1 and P-gp expression. Improving the efficacy of DDP by boosting the miR-145 level provides a new strategy for treatment of ESCC.
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