@Article{Wang2023,
  author          = {Wang, Zhijia and Macakova, Monika and Bugai, Andrii and Kuznetsov, Sergey G. and Hassinen, Antti and Lenasi, Tina and Potdar, Swapnil and Friedel, Caroline C. and Barboric, Matjaz},
  journal         = {Nucleic acids research},
  title           = {P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway.},
  year            = {2023},
  issn            = {1362-4962},
  month           = feb,
  pages           = {1687--1706},
  volume          = {51},
  abstract        = {Positive transcription elongation factor b (P-TEFb) is the crucial player in RNA polymerase II (Pol II) pause release that has emerged as a promising target in cancer. Because single-agent therapy may fail to deliver durable clinical response, targeting of P-TEFb shall benefit when deployed as a combination therapy. We screened a comprehensive oncology library and identified clinically relevant antimetabolites and Mouse double minute 2 homolog (MDM2) inhibitors as top compounds eliciting p53-dependent death of colorectal cancer cells in synergy with selective inhibitors of P-TEFb. While the targeting of P-TEFb augments apoptosis by anti-metabolite 5-fluorouracil, it switches the fate of cancer cells by the non-genotoxic MDM2 inhibitor Nutlin-3a from cell-cycle arrest to apoptosis. Mechanistically, the fate switching is enabled by the induction of p53-dependent pro-apoptotic genes and repression of P-TEFb-dependent pro-survival genes of the PI3K-AKT signaling cascade, which stimulates caspase 9 and intrinsic apoptosis pathway in BAX/BAK-dependent manner. Finally, combination treatments trigger apoptosis of cancer cell spheroids. Together, co-targeting of P-TEFb and suppressors of intrinsic apoptosis could become a viable strategy to eliminate cancer cells.},
  chemicals       = {Phosphatidylinositol 3-Kinases, Positive Transcriptional Elongation Factor B, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53, MDM2 protein, human},
  citation-subset = {IM},
  completed       = {2023-03-09},
  country         = {England},
  doi             = {10.1093/nar/gkad001},
  issn-linking    = {0305-1048},
  issue           = {4},
  keywords        = {Apoptosis; Cell Line, Tumor; Cell Survival; Phosphatidylinositol 3-Kinases, metabolism; Positive Transcriptional Elongation Factor B, antagonists & inhibitors, metabolism; Proto-Oncogene Proteins c-mdm2, genetics; Tumor Suppressor Protein p53, genetics; Humans},
  nlm-id          = {0411011},
  owner           = {NLM},
  pii             = {7023872},
  pmc             = {PMC9976905},
  pmid            = {36727434},
  pubmodel        = {Print},
  pubstate        = {ppublish},
  revised         = {2023-03-09},
}