Nair, RR and Madiwale, SV and Saini, DK (2018) Clampdown of inflammation in aging and anticancer therapies by limiting upregulation and activation of GPCR, CXCR4. In: npj Aging and Mechanisms of Disease, 4 (1).
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Abstract
A sensing protein that is increased in response to DNA damage can be targeted to reduce inflammation and collateral damage during anti-cancer therapy and aging. Scientists at Saini Lab at the Indian Institute of Science have identified the protein that drives sustained and detrimental inflammation when the DNA of cells are damaged, such as during normal human aging or during anti-cancer therapy. Furthermore, blocking the functions of this protein and associated pathway was able to reduce the inflammation to less harmful levels. This discovery could potentially enable safer and more effective anti-cancer therapy by protecting non-cancerous cells surrounding tumors from lethal inflammation. Further studies on this protein could also reduce age associated inflammation, allowing us to age gracefully and healthily. © 2018, © 2018, The Author(s). One of the major pathological outcomes of DNA damage during aging or anticancer therapy is enhanced inflammation. However, the underlying signaling mechanism that drives this is not well understood. Here, we show that in response to DNA damage, ubiquitously expressed GPCR, CXCR4 is upregulated through the ATM kinase-HIF1α dependent DNA damage response (DDR) signaling, and enhances inflammatory response when activated by its ligand, chemokine CXCL12. A pharmacologically active compound screen revealed that this increased inflammation is dependent on reduction in cAMP levels achieved through activation of Gαi through CXCR4 receptor and PDE4A. Through in vivo analysis in mice where DNA damage was induced by irradiation, we validated that CXCR4 is induced systemically after DNA damage and inhibition of its activity or its induction blocked inflammation as well as tissue injury. We thus report a unique DNA damage-linked inflammatory cascade, which is mediated by expression level changes in a GPCR and can be targeted to counteract inflammation during anticancer therapies as well as aging.
| Item Type: | Journal Article |
|---|---|
| Publication: | npj Aging and Mechanisms of Disease |
| Publisher: | Nature Publishing Group |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Department/Centre: | Division of Biological Sciences > Molecular Reproduction, Development & Genetics Division of Interdisciplinary Sciences > Centre for Biosystems Science and Engineering |
| Date Deposited: | 23 Aug 2022 10:00 |
| Last Modified: | 23 Aug 2022 10:00 |
| URI: | https://eprints.iisc.ac.in/id/eprint/76200 |
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