contributed equally to this work.
Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: type 2 diabetes mellitus (T2DM); white adipose tissue (WAT); monocyte chemotactic protein-1 (MCP-1); diet-induced obesity (DIO); macrophage inflammatory protein-1α (MIP-1α); macrophage antigen-1 (MAC-1); thiazolidinedione (TZD).
contributed equally to this work.
Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: type 2 diabetes mellitus (T2DM); white adipose tissue (WAT); monocyte chemotactic protein-1 (MCP-1); diet-induced obesity (DIO); macrophage inflammatory protein-1α (MIP-1α); macrophage antigen-1 (MAC-1); thiazolidinedione (TZD).
Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.
The Myc protein and proteins that participate in mitosis represent attractive targets for cancer therapy. However, their potential is presently compromised by the threat of side effects and by a lack of pharmacological inhibitors of Myc. Here we report that a circumscribed exposure to the aurora kinase inhibitor, VX-680, selectively kills cells that overexpress Myc. This synthetic lethal interaction is attributable to inhibition of aurora-B kinase, with consequent disabling of the chromosomal passenger protein complex (CPPC) and ensuing DNA replication in the absence of cell division; executed by sequential apoptosis and autophagy; not reliant on the tumor suppressor protein p53; and effective against mouse models for B-cell and T-cell lymphomas initiated by transgenes of MYC. Our findings cast light on how inhibitors of aurora-B kinase may kill tumor cells, implicate Myc in the induction of a lethal form of autophagy, indicate that expression of Myc be a useful biomarker for sensitivity of tumor cells to inhibition of the CPPC, dramatize the virtue of bimodal killing by a single therapeutic agent, and suggest a therapeutic strategy for killing tumor cells that overexpress Myc while sparing normal cells.apoptosis | aurora kinase | autophagy synthetic lethality | targeted therapy | chromosomal passenger protein complex
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