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• W2000618585 abstract "Lung cancer is the leading cause of death from cancer worldwide. A challenge of most lung cancer therapies is that lung cancers confer resistance after a first line of treatment, molecular mechanisms of drug-resistance still remain unclear. Understanding the resistance mechanisms and exploring therapeutic targets is crucial to circumventing this challenge in lung cancer treatment. Using microarray analysis, we have found that IGFBP3 was significantly down regulated in cisplatin-resistant lung cancer cells, making it a molecule of interest in circumventing lung cancer resistance. Two lung cancer cell lines were studied, chosen based on their relative resistance to cancer therapies (radiation and cisplatin): HCC2429 as a sensitive model and H460 as a resistant model. IGFBP3 was overexpressed using an adenovirus. Cell survival in two experimental groups (IGFBP3-overexpression and IGFBP3-overexpression plus cisplatin) was analyzed by MTS assay. Signaling changes of p-STAT3, p-ERK, and p-AKT were measured using immunoblotting. Clonogenic assays were used to demonstrate radiation survival sensitivity in HCC2429 and H460 cell lines overexpressing IGFBP3. Overexpression of IGFBP3 in HCC2429 lung cancer cells inhibited cell survival by ∼50% (control = 100% survival), while only having a slight impact on the H460 cell line. When combined with cisplatin, IGFBP3-overexpression synergistically inhibited cell survival in HCC2429 cells by roughly 80%, and to a lesser extent in H460 cells. Overexpression of IGFBP3-GGG, a mutant that fails to bind to IGF, does not fully abolish the inhibition of cell survival by IGFBP3. Signaling profiling reveals that HCC2429 cells have higher IGF1R signaling and lower p-STAT3 signaling than H460 cells. Addition of IGFBP3 blocks IGF1R signaling and p-ERK signaling in HCC2429 cells and induces caspase-3 cleavage. Combined treatment (IGFBP3 and cisplatin) in HCC2429 cells inhibits IGF1R, p-ERK, and p-AKT, leading to apoptotic cell death. In H460 cells, combination treatment inhibits p-STAT3 and p-AKT, but does not induce apoptotic cell death. However, clonogenic assays showed that IGFBP3-overexpression sensitizes H460 cells to radiation treatment (DER = 1.58) and to a lesser extent in HCC2429 cells (DER = 1.09). IGFBP3 synergistically induces cell death with cisplatin in relatively sensitive lung cancer cells (HCC2429), while it also sensitizes the relatively resistant cells (H460) with prolonged treatment when combined with radiation. These data indicates that IGFBP3 is a promising therapeutic target in lung cancer treatment and further investigation is warranted into its molecular mechanism in lung cancer resistance." @default.
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• W2000618585 date "2014-09-01" @default.
• W2000618585 modified "2023-09-27" @default.
• W2000618585 title "IGFBP3 Promotes Cell Death and Sensitizes Cisplatin and Radiation Treatments in Lung Cancer Cell Models" @default.
• W2000618585 doi "https://doi.org/10.1016/j.ijrobp.2014.05.2323" @default.
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