Involvement of nuclear JAK2 signaling in AG490-induced apoptosis of gastric cancer cells

Abstract

Although JAK2 inhibitors can result in antitumor activity against various tumors, some tumors have showed insensitivity or resistance to the inhibitors. To investigate the possible mechanisms underlying responses of gastric cancer (GC) cells to AG490, a specific JAK2 inhibitor, human GC cell lines SGC7901 and AGS were used. AG490 did not significantly induce apoptosis in SGC7901 cells, but it did in AGS cells. Interestingly, in SGC7901 cells, AG490 led to increased nuclear translocation of total JAK2 proteins, accompanied with initial inactivation but later reactivation of JAK2. However, in AGS cells, AG490 led to decreased nuclear localization of total JAK2 proteins, accompanied with sustained inactivation of JAK2. Moreover, silencing of human homolog of Drosophila Hairy and enhancer of split (Hes) 1 with siRNA partly blocked AG490-induced nuclear translocation of JAK2, and enhanced AG490-induced apoptosis in SGC7901 cells. The results collectively suggested that nuclear JAK2 signaling pathway may act as an escape way from JAK2 inhibitors in some GC cells.

Keywords: AG490; Hes1; STAT3; gastric cancer; nuclear JAK2.