Innately Malignant?

Abstract

Chien et al . investigated pathways downstream of Ras-related guanosine triphosphatase B (RalB), which has been implicated in Ras-induced oncogenic transformation, and unearthed a link between oncogenesis and the innate immune response. An RNAi screen revealed that, like RalB depletion, depletion of Sec5 (a component of the exocyst complex, which is involved in tethering secretory vesicles to the plasma membrane) induced apoptosis in human tumor-derived cell lines but not in nontumorigenic epithelial cells. Analysis of the exocyst complex revealed the atypical IκB kinase TBK1 (Tank binding kinase 1, a known component of the innate immune response), which bound to Sec5 in in vitro assays and coimmunoprecipitated with it from HEK293 cells; moreover, TBK1 depletion stimulated apoptosis in tumor-derived cells. Mouse embryo fibroblasts (MEFs) lacking TBK1 were more likely than wild-type MEFs to undergo apoptosis in response to oncogenic K-ras and were less likely to undergo oncogenic transformation, whereas expression of catalytically inactive TBK1 in conjunction with oncogenic K-ras promoted apoptosis. A constitutively active form of Ral promoted TBK1 association with Sec5, enhanced TBK1-dependent phosphorylation of IRF-3 (interferon regulatory factor-3), and stimulated Sec5- and TBK1-dependent nuclear translocation of IRF-3. Both polyinosine-polycytidylic acid [poly(I:C), a mimic of viral dsRNA] and Sendai virus activated endogenous RalB in human bronchial epithelial cells; Sec5 depletion inhibited poly(I:C)- and Sendai virus-dependent translocation of IRF-3 and activation of target genes. Drosophila with a single copy of dSec5 or a hypomorphic mutation of dRal showed an attenuated response to fungus. Thus, the RalB-Sec5-TBK1 connection appears to link innate immune signaling to cancer cell survival. Mantovani and Balkwill discuss the results in the context of the known relationship between inflammation and cancer. Y. Chien, S. Kim, R. Bumeister, Y.-M. Loo, S. W. Kwon, C. L. Johnson, M. G. Balakireva, Y. Romeo, L. Kopelovich, M. Gale Jr., C. Yeaman, J. H. Camonis, Y. Zhao, M. A. White, RalB GTPase-mediated activation of the IκB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell 127 , 157-170 (2006). [PubMed] A. Mantovani, F. Balkwill, RalB signaling: A bridge between inflammation and cancer. Cell 127 , 42-44 (2006). [PubMed]