Bortezomib induces autophagy in head and neck squamous cell carcinoma cells via JNK activation.

The molecular mechanism of autophagy induction following proteasome inhibition is not fully understood. We report that the proteasome inhibitor bortezomib potently induces autophagy in head and neck squamous cell carcinoma (HNSCC) cells, as demonstrated by autophagosome formation and induction of complete autophagic flux. Bortezomib treatment led to phosphorylation/activation of jun N-terminal kinase (JNK) enzymes and JNK-dependent phosphorylation of Bcl-2 on serine 70. Pharmacologic inhibition of JNK, but not p38 MAPK, dramatically inhibited bortezomib induction of autophagy regulatory proteins and autophagosome formation. These results demonstrate a key requirement for JNK signaling in the activation of autophagy by bortezomib.