Objective Tumor necrosis factor-related apoptosis-inducing ligand(TRAIL) resistance greatly limits the clinical therapeutic efficacy of TRAIL. Elucidating the molecular mechanism underlying TRAIL resistance will be fundamental to resolving this problem. Methods Nuclear and cytoplasmic protein extraction and immunofluorescence(IF) assay were used to detect changes in heterogeneous nuclear ribonucleoprotein K(hn RNPK) localization in H1299 cells. The evaluation of cell apoptosis in cells transfected with GFP-hn RNPK, GFP-hn RNPK S284/353 A, or GFP-hn RNPK S284/353 D mutant was performed using cleaved caspase-3 antibody. The gene expression of XIAP was tested by quantitative RT-PCR. Results Previously, we reported that hn RNPK antagonized TRAIL-induced apoptosis through inhibition of PKC-mediated GSK3β phosphorylation. In this study, we further demonstrate that TRAIL treatment induces cytoplasmic accumulation of hn RNPK in H1299 cells. The hn RNPK localized in the cytoplasm has a higher capacity to antagonize TRAIL-induced apoptosis. Both ERK1/2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant(GFP-hn RNPK S284/353A) diminish cytoplasmic accumulation of hn RNPK induced by TRAIL. Moreover, we show that XIAP is involved in hn RNPK-mediated TRAIL resistance in H1299 cells. Conclusion Taken together, these results give new insights into the understanding of the molecular mechanism associated with TRAIL resistance in lung adenocarcinoma. Objective Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance greatly limits the clinical therapeutic efficacy of TRAIL. Elucidating the molecular mechanism underlying TRAIL resistance will be fundamental to resolving this problem. Methods Nuclear and cytoplasmic protein extraction and immunofluorescence (IF) assay were used to detect changes in heterogeneous nuclear ribonucleoprotein K (hn RNPK) localization in H1299 cells. The evaluation of cell apoptosis in cells transfected with GFP-hn RNPK, GFP-hn RNPK S284 / 353 A, or GFP-hn RNPK S284 / 353 The gene expression of XIAP was tested by quantitative RT-PCR. Results Previously, we reported that hn RNPK antagonized TRAIL-induced apoptosis through inhibition of PKC-mediated GSK3β phosphorylation. In this study, we further demonstrate that TRAIL treatment induces cytoplasmic accumulation of hn RNPK in H1299 cells. The hn RNPK localized in the cytoplasm has a higher capacity to antagonize TRAIL-induced apoptosis. Both ERK1 / 2 signaling inhibitor U0126 and ERK-phosphoacceptor-site mutant (GFP-hn RNPK S284 / 353A) diminish cytoplasmic accumulation of hn RNPK induced by TRAIL. hn RNPK-mediated TRAIL resistance in H1299 cells. Conclusion Taken together, these results give new insights into the understanding of the molecular mechanism associated with TRAIL resistance in lung adenocarcinoma.