Article ; Online: P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway.
2023 Volume 51, Issue 4, Page(s) 1687–1706
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 ... ...
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. |
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MeSH term(s) | Apoptosis ; Cell Line, Tumor ; Cell Survival ; Phosphatidylinositol 3-Kinases/metabolism ; Positive Transcriptional Elongation Factor B/antagonists & inhibitors ; Positive Transcriptional Elongation Factor B/metabolism ; Proto-Oncogene Proteins c-mdm2/genetics ; Tumor Suppressor Protein p53/genetics ; Humans |
Chemical Substances | Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) |
Language | English |
Publishing date | 2023-02-01 |
Publishing country | England |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 186809-3 |
ISSN | 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048 |
ISSN (online) | 1362-4962 ; 1362-4954 |
ISSN | 0301-5610 ; 0305-1048 |
DOI | 10.1093/nar/gkad001 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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