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Inhibition of the formation of autophagosome but not autolysosome augments ABT‐751‐induced apoptosis in TP53‐deficient Hep‐3B cells

The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel antimicrotubule drug, ABT‐751, in a tumor protein p53 ( TP53)‐deficient hepatocellular carcinoma‐derived Hep‐3B cells. A series of in vitro assays indicated that ABT‐751 caused the disruption of the mitotic spindle structure, collapse of mitochondrial membrane potential, generation of reactive oxygen species, DNA damage, G 2/M cell cycle arrest, inhibition of anchorage‐independent cell growth and apoptosis in Hep‐3B cells accompanied by alteration of the expression levels of several DNA damage checkpoint proteins and cell cycle regulators. Subsequently, ABT‐751 triggered apoptosis along with markedly upregulated several proapoptotic proteins involving in extrinsic, intrinsic, and caspase‐mediated apoptotic pathways. A pan‐caspase inhibitor suppressed ABT‐751‐induced apoptosis. ABT‐751 also induced autophagy soon after the occurrence of apoptosis through the suppression of AKT serine/threonine kinase/mechanistic target of rapamycin signaling pathway. Exogenous expression of the TP53 gene significantly incurred both apoptosis and autophagy in Hep‐3B cells. Pharmacological inhibition of autophagosome (early autophagy) but not autolysosome (late autophagy) enhanced ABT‐751‐induced apoptosis in TP53‐deficient Hep‐3B cells. Our study provided a new strategy to augment ABT‐751‐induced apoptosis in TP53‐deficient cells.