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Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

Abstract

The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression of many genes that regulate hormone release, cell division, sleep-awake cycle and tumor growth. We demonstrate that ATF4 is a direct target of Clock, and that Clock is overexpressed in cisplatin-resistant cells. Furthermore, Clock expression significantly correlates with cisplatin sensitivity, and that the downregulation of either Clock or ATF4 confers sensitivity of A549 cells to cisplatin and etoposide. Notably, ATF4-overexpressing cells show multidrug resistance and marked elevation of intracellular glutathione. The microarray study reveals that genes for glutathione metabolism are generally downregulated by the knockdown of ATF4 expression. These results suggest that the Clock and ATF4 transcription system might play an important role in multidrug resistance through glutathione-dependent redox system, and also indicate that physiological potentials of Clock-controlled redox system might be important to better understand the oxidative stress-associated disorders including cancer and systemic chronotherapy.

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Acknowledgements

We thank Dr Rich Simon and Amy Peng for providing the BRB ArrayTools software. The free software was very useful and developed for user-friendly applications. This work was supported in part by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Mext), Kakenhi (13218132 and 18590307) and a Grant-in-Aid for Cancer Research from the Fukuoka Cancer Society, Japan.

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Correspondence to K Kohno.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Igarashi, T., Izumi, H., Uchiumi, T. et al. Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines. Oncogene 26, 4749–4760 (2007). https://doi.org/10.1038/sj.onc.1210289

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