The Investigation Of STAT3 Signaling In Gastric Cancer Drug Resistance And Therapy

Gastric cancer(GC)is one of the most common types of cancer worldwide,especially in Asia countries.Although drug resistance poses a great challenge to clinicians,chemotherapy remains the primary treatment for both resettable and advanced gastric cancer.Our research focused on the mechanism of induction of drug resistance of GC and discovering new target for clinical treatmen of GC.In our study,a tissue chip and multiple GC cell lines was adopted to evaluate the relationship of constituted activated STAT3 and GC chemo drug resistance ability.We observed that S1PR1 and phosphor STAT3 shown significantly correlation in gastric tumor tissues,indicating the expression of S1PR1 might cause STAT3 constituted activation in the drug resistance tumor cells.In vitro assay shown that high expression of S1PR 1 was albe to induce STAT3 phosphorylation and tumor cell drug resistance,either by SIP activation or S1PR1 overexpression.Knock down of S1PR 1 reduced STAT3 phosphorylation,and down regulated the expression of STAT3 targeting genes and significantly sensitize tumor cell to chemo drug.FTY720,a S1PR1 inhibitor combined with chemo drug inhibited tumor growth and induced massive tumor cell apoptosis both invitro and in vivo.And its effect is aslo S1PR1 dependent.Luteolin is a natural flavonoid abundant in various fruits and vegetables.It has various biological activities such as anti-inflammation,anti-oxidant and anti-tumor et al.However,the anti-tumor effect of luteolin,in gastric cancer(GC)cells has not been fully understood.Here we show that luteolin selectively kills STAT3 over activated GC cells that are often drug resistant.The treatment of luteolin in GC cells significantly inhibited STAT3 phosphorylation and reduced the expression of STAT3's targeting genes without the upregulation of STAT3 negative regulators like PIAS and SOCS3 in a dose dependent manner.Silencing of SHP-1,a protein tyrosine phosphatase,abolished the effect of luteolin on STAT3 and luteolin induced GC cell apoptosis,suggesting that SHP-1 mediated the anti-tumor effects of luteolin.Further studies revealed that luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3,which promoted the interacting between SHP-1 and STAT3,and enhanced the dephosphorylation of STAT3 by SHP-1.And this result was consistent with our previous finding about HSP-90's effect on STAT3 phosphorylation.GC cells xenograft mouse model confirmed that luteolin significantly inhibited STAT3 high activated tumor growth in vivo but have fewer effect on STAT3 low activated tumors.In conclusion,our results defined a novel mechanism for the induction of persistent STAT3 activation through S1PR1 in drug resistant tumor cells.HSP-90 maitained the constituete activation of STAT3.The inhibition of S1PR1 by FTY720 and targeting HSP-90 by luteolin can specificity kill these STAT3 high activated tumor cells with a high efficiency.Our findings may provide a new target for the treatment of drug resistant GCs.