Gas6/MerTK signaling is negatively regulated by NF- κB and supports lung carcinogenesis.

Gas6/MerTK signaling is negatively regulated by NF-κB and supports lung carcinogenesis. Oncotarget. 2019 Dec 17;10(66):7031-7042 Authors: Novitskiy SV, Zaynagetdinov R, Vasiukov G, Gutor S, Han W, Serezani A, Matafonov A, Gleaves LA, Sherrill TP, Polosukhin VV, Blackwell TS Abstract Growth arrest-specific 6 (Gas6) has been implicated in carcinogenesis through activation of its receptors, particularly MerTK. To investigate whether Gas6 plays a role in resistance to NF-κB inhibitors, which have not proven to be effective agents for lung cancer therapy, we studied lung cancer models induced by urethane injection or expression of mutant Kras (KrasG12D). We found that Gas6 is primarily produced by macrophages during tumorigenesis and that Gas6 is negatively regulated by NF-κB. Since Gas6 is a vitamin K dependent protein, we used low-dose warfarin to block Gas6 production and showed that this treatment inhibited tumorigenesis in both the urethane and KrasG12D models, most prominently in mice with targeted deletion of IKKβ in myeloid cells (IKKβΔMye mice). In addition, MerTK deficient mice had reduced urethane-induced tumorigenesis. Inhibition of the Gas6-MerTK pathway in all these models reduced macrophages and neutrophils in the lungs of tumor-bearing mice. Analysis of mouse lung tumors revealed MerTK staining on tumor cells and in vitro studies showed that Gas6 increased proliferation of human lung cancer cell lines. To assess the ...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research