ATG7-dependent and independent autophagy determine the type of treatment in lung cancer.

ABSTRACT

Based on the role of ATG7 in the initiation of autophagy, autophagy can be divided into ATG7-dependent selective autophagy and ATG7-independent alternative autophagy. However, the detailed roles of two different types of autophagy in antitumor therapy have not been fully elucidated so far. Here, we for the first time demonstrated an investigational inducer, w09, could induce both selective autophagy and alternative autophagy in NSCLC, but the phenotypes of these two kinds of autophagy are different：(1) w09-induced selective autophagy mainly promoted cell apoptosis, while w09-triggered alternative autophagy markedly induced autophagic cell death in NSCLC；(2) w09-induced ATG7 dependent autophagy mainly promoted the accumulation of SQSTM1/p62, while w09-triggered ATG7 independent autophagy markedly accelerated the degradation of SQSTM1/p62. These above results were further confirmed by knockout ATG7 gene in A549 cells or restoration of ATG7 function in H1650 cells. Deletion of ATG7 gene markedly attenuated the effect of w09-induced autophagy or apoptosis on A549 cells, while restoration of functional ATG7 markedly enhanced the effect of w09-induced autophagy and apoptosis on H1650 cells. Mechanistically, we further revealed that w09 induced two different types of autophagy through inhibiting PI3K/AKT/mTOR signaling pathway. Notably, compared with A549WT xenograft model, the in vivo antitumor effect of w09 or Taxel on the ATG7-deficient A549 xenograft model was significantly attenuated. Therefore, a special attention must be paid to distinguish which kinds of autophagy have been induced by autophagy inducers with antitumor agents by targeting PI3K/AKT/mTOR signaling pathway.