The Mechanism Underlying Cordycepin Inhibits Pancreatic Cancer

Cordyceps militaris is the mycelium of Cordyceps militaris(L.)Link belonging to cordycipitaceae.Cordyceps militaris is the traditional Chinese medicine for treating tumor and immune disease.The cordycepin is active compound in cordyceps militaris with various biological activities including anti-inflammation,anti-tumor,antibiosis and immunoregulation.However,the mechanism underlying cordycepin induces pancreatic cancer cell apoptosis in vitro and in vivo remains vague.In this study,we demonstrated that cordycepin selectively inhibited the growth,migration and clone formation of BxPC-3 cells while it has no effect on pancreatic cell line HPDE6-C7 at its effective concentration(100 ?M)on Bx PC-3 cells.Moreover,cordycepin could induce BxPC-3 cells apoptosis and cycle arrest based on measurement by Flow cytometry.Mechanism study indicated that TRAF2,cytochrome c,caspase-3 and caspase-9 were activated by cordycepin to induce cell apoptosis.Besides,cordycpein might cause S phase arrested via inducing the phosphorylation of ATM and ATR and influencing the expression of cell cycle related protein,such as p21.Meanwhile,cordycepin also activated MAPK(p38,JNK)and NF-?B signaling pathway to impede BxPC-3 cell growth.Surface Plasmon Resonance(SPR)was employed to explore and comfirm the bioactive target molecule of cordycepin.The SPR analyses showed that cordycepin could strongly bind to FGFR2(KD value = 7.77 × 10-9).In addition,and cordycepin impaired FGF-induced Bx PC-3 cells growth by MTT assay.Next,we found cordycepin suppressed the phosphorylation of FGFR2 due to the intense interaction between them,to block its downstream ERK MAPK signaling pathway and the expression of transcript factors(c-Myc,c-Fos,stat1),and then inhibited the growth and migration of BxPC-3 cell.In vivo studies suggested that cordycpein(10 mg/kg)via oral administration could inhibit the growth of xenografted pancreatic cancer BxPC-3 cells,while the tumor inhibitory rate is about 60%.Surprisingly,it had no toxicity on the body weight of mice.Immunohistochemistry and Western blotting assay analysis demonstrated that cordycepin might inhibit ERK MAPK signaling pathway to disrupt tumor growth.In summary,to our knowledge we not only first detected cordycepin could impede the pancreatic cancer cell BxPC-3 in vitro and in vivo,but also found that cordycepin targeted FGFR2 to impede ERK MAPK signaling pathway and inhibit Bx PC-3 cells growth.These studies pave the way for new drug development based on effect of cordycepin on anti-pancreatic cancer.