ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts.

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.

• Authors: M N Washington, G Suh, A F Orozco, M N Sutton, H Yang, Y Wang, W Mao, S Millward, A Ornelas, N Atkinson, W Liao, R C Bast Jr, Z Lu
• Journal: Cell death & disease (Cell Death Dis) Vol. 6 Pg. e1836 (Aug 06 2015) ISSN: 2041-4889 [Electronic] England
• PMID: 26247722 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AGFG1 protein, human
• Antineoplastic Agents
• BCL2 protein, human
• DIRAS3 protein, human
• Nuclear Pore Complex Proteins
• Proto-Oncogene Proteins c-bcl-2
• RNA-Binding Proteins
• Reactive Oxygen Species
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• Chloroquine
• Poly(ADP-ribose) Polymerases
• ERBB2 protein, human
• Receptor, ErbB-2
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• MAPK1 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Caspase 3
• rho GTP-Binding Proteins
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Autophagy (drug effects, genetics)
• Caspase 3 (genetics, metabolism)
• Cell Line, Tumor
• Chloroquine (pharmacology)
• Cisplatin (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Mitogen-Activated Protein Kinase 1 (genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Nuclear Pore Complex Proteins (genetics, metabolism)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Poly(ADP-ribose) Polymerases (genetics, metabolism)
• Proteolysis
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays
• rho GTP-Binding Proteins (genetics, metabolism)