Multiple myeloma (MM) is a plasma cell malignancy. The hepatocyte growth factor (HGF) has been demonstrated to promote MM cell growth. NK4, a splice variant of HGF in which the heavy chain consists of the N-terminal domain and the four kringle domains, is a specific antagonist of HGF that competes with HGF for tyrosine-protein kinase receptor binding. The current study aimed to examine the antiproliferative activity of NK4 on human MM cells and to investigate the underlying mechanism. The results indicated that NK4 suppressed proliferation and induced apoptosis in RPMI 8226 cells. In addition, NK4 altered the expression of cell cycle and apoptosis-associated proteins in RPMI 8226, including cyclin-dependent kinase 4, cyclin D1, cyclin-dependent kinase inhibitor 1B, apoptosis regulator Bcl-2, apoptosis regulator BAX, cleaved caspase-9 and caspase-3. Furthermore, NK4 inhibited the activation of the RAC-α serine/threonine-protein kinase (Akt)/serine/threonine-protein kinase mTOR (mTOR) signaling pathway and reduced the levels of phosphorylated (p)-Akt, p-mTOR, ribosomal protein S6 kinase beta-1 and eukaryotic initiation factor 4E binding protein 1 in RPMI 8226 cells. In conclusion, NK4 inhibited the proliferation of human MM RPMI 8226 cells, which may be attributed to the induction of apoptosis and the inhibition of the Akt/mTOR signaling pathway.
Keywords: RAC-α serine/threonine-protein kinase/serine/threonine-protein kinase mTOR; RPMI 8226; hepatocyte growth factor antagonist NK4; multiple myeloma; proliferation.