Find in Library

Compound <b>6d</b>, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory capability remains unclear. Here, we showed that compound <b>6d</b> is an inhibitor of Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis of mitochondria. Regarding the underlying mechanism, we identified HDAC6 as a direct substrate for caspase 3, and caspase 3 activation induced by compound <b>6d</b> directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound <b>6d</b> promoted autophagy initiation by inhibiting interaction between Bcl-2 and Beclin 1, while it led to the accumulation of ubiquitinated proteins and the reduction of autophagic flux. Collectively, our findings reveal that the Bcl-2-caspase 3-HDAC6 cascade is a crucial regulatory pathway of autophagy and identify compound <b>6d</b> as a novel lead compound for disrupting the balance between apoptosis and autophagy.