Two Gln187 mutants of human soluble APRIL inhibit proliferation of lung carcinoma A549 cells
Dai, S.; Zheng, Y.; Chen, B.; Gao, M.; Zhang, Y.; Zhang, L.; Gong, W.; He, F.
Acta Biochimica Polonica 56(4): 703-710
2009
ISSN/ISBN: 0001-527X PMID: 19997650 Document Number: 632963
Soluble APRIL (sAPRIL), the active form of a proliferation-inducing ligand (APRIL), is implicated in the proliferation of tumor cells. Suppressing APRIL function has been considered as a potential strategy for the therapy of APRIL-associated tumors. In the present study, we generated human sAPRIL and its two mutants, Gln187-D-sAPRIL (Gln187 deleted) and Gly187-sAPRIL (Gln187 replaced by Gly). In vitro experiments showed that the two mutants had similar specific binding capacity to lung carcinoma A549 cells compared to the wild-type sAPRIL, and both, especially Gly187-sAPRIL, exhibited significant antagonistic effect on sAPRIL-induced tumor cell proliferation in a dose-dependent manner, which might be predominantly mediated by blocking sAPRIL-induced MEK and ERK phosphorylation but not p38MAPK or JNK signaling. In vivo experiments with nude mice bearing A549 cell-derived xenograft tumor showed that only the Gly187-sAPRIL mutant could significantly suppress the tumor growth. These results suggest that Gln187 may be a crucial amino acid in APRIL-mediated tumor cell proliferation via the MEK-ERK signaling pathway and that the sAPRIL mutants may serve as novel potential antagonists of APRIL for the therapy of APRIL-associated cancers.