Abstract
Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype and so far, no favorable therapeutic strategy has been established for chemo-resistant SCLC. Cisplatin is one of the most important components among all standard poly-chemotherapeutic regimens for SCLC; therefore, this study focused on revealing Cisplatin-resistance mechanism(s) in this disease. Cisplatin-resistant SCLC cells were generated in the NCI-H69 xenograft model in nude mice by continuous intravenous administration of Cisplatin; Cisplatin resistance of the tumor cells was confirmed by in vitro and in vivo tests, and the gene expression profile of the resistant cells was determined using microarray analysis. A significantly higher expression of tribbles pseudokinase 2 (TRIB2) mRNA in the Cisplatin-resistant cells was found compared to parental H69 cells. Further, the Cisplatin-resistance level was decreased when TRIB2 expression was knocked down. The mRNA and protein levels of CCAAT/enhancer binding protein alpha (CEBPA), known to be a transcription factor regulating cell differentiation and a target for degradation by TRIB2, as well as selected cancer stem cell makers in the Cisplatin-resistant cells, were measured. We found that CEBPA protein levels could be upregulated by knocking down the overexpressed TRIB2, which also reversed the Cisplatin-resistance of these cells; further, the Cisplatin-resistant SCLC cells demonstrated certain cancer stem cell-like properties. Similar patterns were also observed in limited human tumor specimens of chemo-resistant SCLC patients: namely, overexpressed TRIB2 and undetected CEBPA proteins. Our study revealed a possible molecular mechanism for Cisplatin-resistant SCLC involving induced TRIB2 overexpression and downregulation of CEBPA protein. We propose that this mechanism is a potential therapeutic target to circumvent chemo-resistance in SCLC.
Highlights
Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype with only rare long-term survival [1] [2]
We found that CCAAT/enhancer binding protein alpha (CEBPA) protein levels could be upregulated by knocking down the overexpressed tribbles pseudokinase 2 (TRIB2), which reversed the Cisplatin-resistance of these cells; further, the Cisplatin-resistant SCLC cells demonstrated certain cancer stem cell-like properties
We selected TRIB2 for further study, both because it has been reported as an oncogene and because we found that the TRIB2 gene was upregulated the most among all the Cisplatintreated mice (Supplementary Data 3) with p value < 0.05 (Figure 3A)
Summary
Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype with only rare long-term survival [1] [2]. Several abnormalities have previously been found contributing to these chemo-resistance mechanisms. These include 1) dysregulation of apoptosis linked to Bcl2, 2) extracellular matrix (ECM)-mediated anti-apoptotic www.impactjournals.com/oncotarget effects on SCLC cells, and 3) acquisition of cancer stem cell (CSC)-like properties. Overexpression of Bcl-2 was found to be parallel to Cisplatin resistance, and bcl-2 stable transfection strongly reduced Cisplatin sensitivity in SCLC cells [6]. Osteopontin stable transfection resulted in a higher ratio of Bcl-2/Bax and lower activation of caspase-9 and caspase-3 following Cisplatin treatment [7]. Bcl2associated athanogene 3 (BAG3) expression was detected in SCLC cell lines as well as in SCLC patient samples, and siRNA down-regulation of BAG3 sensitized SCLC cells to Cisplatin treatment [8]
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