Inhibition of autophagy potentiates the anti‐metastasis effect of phenethyl isothiocyanate through JAK2/STAT3 pathway in lung cancer cells

Phenethyl isothiocyanate (PEITC) is a natural compound abundant in cruciferous vegetables. PEITC possesses anti-tumor effect in various human malignances. Our previous study has shown that benzyl isothiocyanates (BITC) induce autophagy in lung cancer cells. However, whether autophagy play a role in the inhibitory effect of PEITC on lung cancer metastasis is unclear. In this study, we found that PEITC suppressed migration and invasion of lung cancer cells by regulating MMP2. It also induced autophagy, evidenced by the formation of acidic vesicular organelles (AVOs), the punctate pattern of LC3, the accumulation of LC3-II, and the expression of Beclin-1. Inhibition of autophagy by 3-MA and chloroquine (CQ) or knock down of Beclin-1 enhanced PEITC-caused metastasis inhibition. JAK2/STAT3 pathway was suppressed by PEITC, and further inhibited by 3-MA and CQ or Beclin-1 knock down, as a result of decreased expression of p-JAK2 and p-STAT3. Blocking JAK2/STAT3 pathway by inhibitor AG490 and Stattic suppressed cell migration and decreased the expression of MMP2, MMP9, Twist, and c-Myc. Further in vivo study showed that PEITC inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3 pathway, and inhibitor CQ enhanced this effect. Taken together, our results demonstrate that PEITC inhibits metastasis potential of lung cancer cells, and induces autophagy. The autophagy induced by PEITC preserves metastasis potential of lung cancer cells, via activation of JAK2/STAT3 pathway. Inhibition of autophagy enhanced the inhibitory effect of PEITC on metastasis potential of lung cancer cells. Our finding suggests that targeting autophagy could be a promising strategy for anti-metastasis therapies.