Two Gln187 mutants of human soluble APRIL inhibit proliferation of lung carcinoma A549 cells.
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.
Dai
Shuangshuang
S
Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China.
Zheng
Yingru
Y
Chen
Bin
B
Gao
Min
M
Zhang
Yan
Y
Zhang
Li
L
Gong
Wei
W
He
Fengtain
F
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000502:physiology; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C114631:TNFSF13 protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D005973:Glutamine; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases