Arkasubhra Ghosh1, Gaye Saginc2, Shi Chi Leow1, Ekta Khattar1, Eun Myong Shin1, Ting Dong Yan3, Marc Wong1, Zhizhuo Zhang4, Guoliang Li5, Wing-Kin Sung4,5, Jianbiao Zhou6, Wee Joo Chng6, Shang Li3, Edison Liu2 and Vinay Tergaonkar1
1- Laboratory of NFκB Signaling, IMCB, Proteos, Singapore 138673.
2- Cancer Biology and Pharmacology, Genome Institute of Singapore.
3- Department of Cancer Biology, DUKE-NUS, Singapore.
4- School of Computing, National University of Singapore.
5- Computational and Systems Biology, Genome Institute of Singapore.
6- Cancer Science Institute of Singapore.
Published in Nature Cell Biology on 18 November 2012.
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Chronic Inflammation, such as that triggered by infectious agents is a key driver of human cancers. Two sets of Nobel prizes were awarded in last 7 years; (a) to discovery of Helicobacter as the initiating agent of gastric cancers (2005) and (b) to the finding that infection with high risk Human Papilloma Virus inevitably leads to development of cervical cancers (2008). However, even in cancers not initiated by these infectious agents, inflammation is now known to be the key driver of cancer initiation and progression. That is why people on asprin (an anti-inflammatory drug) have significantly lower risk of some cancers and on the other hand, obese individuals (who have chronic inflammation), are at greater risk of certain kinds of cancers even if they do not have these infectious aeitiologies. But what activates and sustains chronic inflammation in cancers is not understood at all. Another hallmark of all human cancers is that cancer cells divide endlessly and for this, they need an enzyme called telomerase (discovery of which received the Nobel prize in 2009). Many pieces of evidence, however, suggest that making cells divide endlessly although necessary, is not the only attribute that the telomerase enzyme imparts to cancer cells. Now we show for the first time that telomerase enzyme, is the key missing link that in addition to its role in cell division also kick starts and maintains chronic inflammation in cancers. These results provide a unified reason for the co-existance of chronic inflammation and telomerase activity seen in almost all cancers. Our findings also have immense therapeutic implications. Drugs blocking telomerase are showing promising results in blocking cancer inflammation and cancer progression in Singapore.
Figure Legend: A model based on our studies. In resting cells, NF-κB-dependent gene transcription regulates proliferation, resistance to apoptosis and innate immune responses. This pathway is rapidly turned off because of feedback mechanisms such as synthesis of IκB proteins and the action of phosphatases and de-ubiquitinases. However, in cancer cells, which require sustained and enhanced activity of NF-κB target genes, reactivated hTERT (which is a NF-κB target gene itself), a limiting factor for telomerase activity, stabilizes p65 on a subset of target gene promoters and increases the expression of NF-κB target genes that drive invasion, cellular proliferation and resistance to apoptosis, all necessary hallmarks of cancer. In addition, these cancer cells secrete chemokines attracting macrophages that produce more NF-κB activating cytokines. Hence, this feed-forward pathway sustains levels of NF-κB as well as telomerase at a critical level. Eventually, both telomere-dependent and -independent activities of telomerase may aid in the process of transformation.
For more information on Vinay TEGAONKAR’s laboratory, please click here.