title: Deregulated G1-S control and energy stress contribute to the synthetic-lethal interactions between inactivation of RB and TSC1 or TSC2.
abstract: Synthetic lethality is a potential strategy for cancer treatment by specifically promoting the death of cancer cells with particular defects such as the loss of the RB (RB1) tumor suppressor. We previously showed that inactivation of both RB and TSC2 induces synergistic apoptosis during the development of Drosophila melanogaster and in cancer cells. However, the in vivo mechanism of this synthetic-lethal interaction is not clear. Here, we show that synergistic cell death in tissues that have lost the RB and TSC orthologs rbf and dtsc1/gig, respectively, or overexpress Rheb and dE2F1, are correlated with synergistic defects in G1-S control, which causes cells to accumulate DNA damage. Coexpression of the G1-S inhibitor Dap, but not the G2-M inhibitor dWee1, decreases DNA damage and reduces cell death. In addition, we show that rbf and dtsc1 mutant cells are under energy stress, are sensitive to decreased energy levels and depend on the cellular energy stress-response pathway for survival. Decreasing mitochondrial ATP synthesis by inactivating cova or abrogating the energy-stress response by removing the metabolic regulator LKB1 both enhance the elimination of cells lacking either rbf or dtsc1. These observations, in conjunction with the finding that deregulation of TORC1 induces activation of JNK, indicate that multiple cellular stresses are induced and contribute to the synthetic-lethal interactions between RB and TSC1/TSC2 inactivation. The insights gained from this study suggest new approaches for targeting RB-deficient cancers.
authors: Ben May Department for Cancer Research, The University of Chicago, 929 E. 57th Street, Chicago, IL 60637, USA.
authors: Gabriel M
authors: GM
authors: Gordon
authors: Tianyi
authors: T
authors: Zhang
authors: Jiong
authors: J
authors: Zhao
authors: Wei
authors: W
authors: Du
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D004734:Energy Metabolism / Q000502:physiology*; D016193:G1 Phase / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; C099965:Rbf protein, Drosophila; D016160:Retinoblastoma Protein; C570998:TORC1 protein complex, Drosophila; C515347:TSC1 protein, Drosophila; D014157:Transcription Factors; C117726:gig protein, Drosophila; D011494:Protein Kinases; C495775:LKB1 protein, Drosophila; D000091162:AMP-Activated Protein Kinase Kinases; D048670:MAP Kinase Kinase 4
keywords: Cell death; Energy stress; G1–S control; LKB1; RB; TSC1; TSC2; Tumor