Abstract
Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Autophagy / drug effects*
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Autophagy / genetics
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Line, Tumor
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Chloroquine / pharmacology
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Cisplatin / pharmacology*
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Female
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G1 Phase Cell Cycle Checkpoints / drug effects
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Gene Expression Regulation, Neoplastic*
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Humans
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Nuclear Pore Complex Proteins / genetics
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Nuclear Pore Complex Proteins / metabolism
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Proteolysis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Reactive Oxygen Species / metabolism
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Signal Transduction
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism
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Xenograft Model Antitumor Assays
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rho GTP-Binding Proteins / genetics*
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rho GTP-Binding Proteins / metabolism
Substances
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AGFG1 protein, human
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Antineoplastic Agents
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BCL2 protein, human
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DIRAS3 protein, human
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Nuclear Pore Complex Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA-Binding Proteins
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Reactive Oxygen Species
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Chloroquine
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Poly(ADP-ribose) Polymerases
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ERBB2 protein, human
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Receptor, ErbB-2
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RIPK3 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Caspase 3
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rho GTP-Binding Proteins
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Cisplatin