Abstract
Interferon-α (IFN-α) is used clinically to treat hepatocellular carcinoma (HCC), although the detailed therapeutic mechanisms remain elusive. In particular, IFN-α has long been implicated in control of the cell cycle, but its actual point of action has not been clarified. Here, using time lapse imaging analyses of the human HCC cell line HuH7 carrying a fluorescence ubiquitination-based cell cycle indicator (Fucci), we found that IFN-α induced cell cycle arrest in the G0/G1 phases, leading to apoptosis through an IFN-α type-2 receptor (IFNAR2)-dependent signaling pathway. Detailed analyses by time lapse imaging and biochemical assays demonstrated that the IFN-α/IFNAR2 axis sensitizes cells to apoptosis in the S/G2/M phases in preparation for cell death in the G0/G1 phases. In summary, this study is the first to demonstrate the detailed mechanism of IFN-α as an anticancer drug, using Fucci-based time lapse imaging, which will be informative for treating HCC with IFN-α in clinical practice.
Highlights
The mode of action of interferon-␣ has been unknown
Using time lapse imaging analyses of the human hepatocellular carcinoma (HCC) cell line HuH7 carrying a fluorescence ubiquitination-based cell cycle indicator (Fucci), we found that IFN-␣ induced cell cycle arrest in the G0/G1 phases, leading to apoptosis through an IFN-␣ type-2 receptor (IFNAR2)-dependent signaling pathway
These results were in agreement with the time lapse imaging results and suggest that IFN-␣ initiates its action during the S/G2/M phase and that cell cycle arrest and apoptosis occur in the subsequent G0/G1 phase
Summary
The mode of action of interferon-␣ has been unknown. Results: Its point of action in the cell cycle was analyzed by single cell tracking using time lapse confocal imaging. Interferon-␣ (IFN-␣) is used clinically to treat hepatocellular carcinoma (HCC), the detailed therapeutic mechanisms remain elusive. Using time lapse imaging analyses of the human HCC cell line HuH7 carrying a fluorescence ubiquitination-based cell cycle indicator (Fucci), we found that IFN-␣ induced cell cycle arrest in the G0/G1 phases, leading to apoptosis through an IFN-␣ type-2 receptor (IFNAR2)-dependent signaling pathway. This study is the first to demonstrate the detailed mechanism of IFN-␣ as an anticancer drug, using Fucci-based time lapse imaging, which will be informative for treating HCC with IFN-␣ in clinical practice. Aside from the accumulated evidence of its clinical utility, the actual therapeutic mechanisms remain obscure, some previous reports have indicated the significance of cell cycle regulation in the anticancer action of the IFN-␣/IFNAR2 axis. We exploited these advanced imaging technologies to analyze the therapeutic mechanism of IFN-␣ against IFN-␣-susceptible HCCs, in association with the cell cycle
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