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Inhibition of the formation of autophagosome but not autolysosome augments ABT-751-induced apoptosis in TP53-deficient Hep-3B cells.
- Source :
-
Journal of cellular physiology [J Cell Physiol] 2019 Jun; Vol. 234 (6), pp. 9551-9563. Date of Electronic Publication: 2018 Oct 26. - Publication Year :
- 2019
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Abstract
- 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 <subscript>2</subscript> /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.<br /> (© 2018 Wiley Periodicals, Inc.)
- Subjects :
- Autophagosomes drug effects
Autophagy drug effects
Caspases metabolism
Cell Cycle Checkpoints drug effects
Cell Cycle Checkpoints genetics
Cell Line, Tumor
Cell Proliferation drug effects
DNA Damage
Humans
Lysosomes drug effects
Membrane Potential, Mitochondrial drug effects
Mitosis drug effects
Proto-Oncogene Proteins c-akt metabolism
Reactive Oxygen Species metabolism
Signal Transduction drug effects
Sulfonamides chemistry
TOR Serine-Threonine Kinases metabolism
Tumor Suppressor Protein p53 genetics
Apoptosis drug effects
Autophagosomes metabolism
Lysosomes metabolism
Sulfonamides pharmacology
Tumor Suppressor Protein p53 deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4652
- Volume :
- 234
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of cellular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 30367486
- Full Text :
- https://doi.org/10.1002/jcp.27643