TAK1 inhibition by natural cyclopeptide RA-V promotes apoptosis and inhibits protective autophagy in Kras-dependent non-small-cell lung carcinoma cells

TAK1 kinase is required for the survival of Kras-dependent non-small-cell lung carcinoma (NSCLC) cells. Here, we report that the inhibition of TAK1 by a small natural cyclopeptide (RA-V) can promote apoptosis and inhibit protective autophagy in Kras-dependent NSCLC cells. Using short hairpin RNAs to deplete K-Ras, we identified H441 and H358 cells as Kras-dependent NSCLC cells which require protective basal autophagy for cell viability. We found that RA-V could selectively kill and induce apoptosis in H441 and H358 cells but had little effect on A549 and H460 (Kras-independent) cells. Furthermore, RA-V could inhibit basal autophagy in H441 and H358 cells. Mechanistic studies further showed that RA-V inhibits the level of TAK1 phosphorylation by binding directly to TAK1, resulting in the inhibition of the autophagy-related TAK1-AMPK-mTOR pathway. In addition, we found that RA-V could inhibit TAK1-P70S6K interaction, which may also inhibit basal autophagy. Our study shows that RA-V acts as an inducer of apoptosis and inhibitor of autophagy via the inhibition of TAK1 and provides the first example of TAK1 inhibition as a potential therapeutic strategy to promote apoptosis and inhibit protective autophagy in Kras-dependent NSCLC.