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NF-κB and STAT3 cooperatively induce IL6 in starved cancer cells

Oncogene volume 31, pages 3467–3481 (2012)Cite this article

Abstract

A number of genes involved in tumorigenesis have been known to be controlled by signal transducer and activator of transcription 3 (STAT3) and NF-κB, either synergistically or individually. In starved cancer cells, we found that NF-κB was activated through endoplasmic reticulum stress signals, which depend on reactive oxygen species, cytosolic calcium and preserved translation of NF-κB p65 subunit, but independent of IκBα serine phosphorylation, thereby resulting in IL6 induction. STAT3 was required for proper induction of IL6 by NF-κB. They existed as identical nuclear complexes in proximal IL6 promoters, and STAT3 had critical roles in binding to IL6 promoters as well as nuclear retention of NF-κB. The conditioned media from starved cancer cells contained various secretory factors, such as IL6, IL9, VWF (von Willebrand factor), FREM1 (FRAS1 related extracellular matrix 1), SAA1 (serum amyloid A1), SDK1 (sidekick homolog 1) and ADAM12 (ADAM metallopeptidase domain 12), induced by NF-κB and STAT3 and promoted clonogenic capacities of cancer cells, and proliferation and migration of human umbilical vein endothelial cells. These results suggest novel survival strategies of cancer cells by which two oncogenic transcriptional factors, NF-κB and STAT3, are activated simultaneously by an intrinsic mechanism during stressful conditions of cancer cells, and they cooperatively induce various survival factors.

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Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2011-0005804, No. 2009-0076174, and No. 2011-0089971), and a Korea Science and Engineering Foundation (KOSEF) Grant (R13-2003-019) through the Chronic Inflammatory Disease Research Center (CIDRC). We are grateful to Mogam Biotechnology Research Institute (Yongin, Korea) for providing us with HUVEC and U87MG cell lines. We are very thankful to Professor Kyung-Sup Kim (Yonsei University College of Medicine, Seoul, Korea) and Professor Woon Ki Baek for critical reading and proofreading of the manuscript.

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  1. Department of Microbiology, Ajou University School of Medicine, Suwon, Korea

    S Yoon, S U Woo, J H Kang, K Kim, H-J Shin, S Park & Y-J Chwae

  2. Neuro-Oncology Clinic, National Cancer Center Korea, Koyang, Korea

    H-S Gwak

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Yoon, S., Woo, S., Kang, J. et al. NF-κB and STAT3 cooperatively induce IL6 in starved cancer cells. Oncogene 31, 3467–3481 (2012). https://doi.org/10.1038/onc.2011.517

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