P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway

被引:7
作者
Wang, Zhijia [1 ]
Macakova, Monika [1 ]
Bugai, Andrii [1 ,2 ]
Kuznetsov, Sergey G. [3 ]
Hassinen, Antti [4 ]
Lenasi, Tina [1 ]
Potdar, Swapnil [3 ]
Friedel, Caroline C. [5 ]
Barboric, Matjaz [1 ]
机构
[1] Univ Helsinki, Dept Biochem & Dev Biol, FIN-00014 Helsinki, Finland
[2] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus C, Denmark
[3] Univ Helsinki, Inst Mol Med Finland FIMM, High Throughput Biomed Unit HTB, FIN-00014 Helsinki, Finland
[4] Univ Helsinki, Inst Mol Med Finland FIMM, High Content Imaging & Anal Unit HCA, FIN-00014 Helsinki, Finland
[5] Ludwig Maximilians Univ Munchen, Inst Informat, D-80333 Munich, Germany
基金
芬兰科学院;
关键词
CANCER-CELLS; TRANSCRIPTIONAL ADDICTION; EXPRESSION; CDK9; INHIBITOR; PROGRAM; KINASE; GENES; IDENTIFICATION; ANTAGONISTS;
D O I
10.1093/nar/gkad001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1687 / 1706
页数:20
相关论文
共 86 条
[1]   The Establishment of a Hyperactive Structure Allows the Tumour Suppressor Protein p53 to Function through P-TEFb during Limited CDK9 Kinase Inhibition [J].
Albert, Thomas K. ;
Antrecht, Claudia ;
Kremmer, Elisabeth ;
Meisterernst, Michael .
PLOS ONE, 2016, 11 (01)
[2]   Identification of a core TP53 transcriptional program with highly distributed tumor suppressive activity [J].
Andrysik, Zdenek ;
Galbraith, Matthew D. ;
Guarnieri, Anna L. ;
Zaccara, Sara ;
Sullivan, Kelly D. ;
Pandey, Ahwan ;
MacBeth, Morgan ;
Inga, Alberto ;
Espinosa, Joaquin M. .
GENOME RESEARCH, 2017, 27 (10) :1645-1657
[3]   Targeting Apoptosis Pathways for New Cancer Therapeutics [J].
Bai, Longchuan ;
Wang, Shaomeng .
ANNUAL REVIEW OF MEDICINE, VOL 65, 2014, 65 :139-155
[4]   Transcriptional Regulation by p53 [J].
Beckerman, Rachel ;
Prives, Carol .
COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2010, 2 (08) :a000935
[5]   CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].
BENJAMINI, Y ;
HOCHBERG, Y .
JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300
[6]   Coupling mRNA processing with transcription in time and space [J].
Bentley, David L. .
NATURE REVIEWS GENETICS, 2014, 15 (03) :163-175
[7]   The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes [J].
Blazek, Dalibor ;
Kohoutek, Jiri ;
Bartholomeeusen, Koen ;
Johansen, Eric ;
Hulinkova, Petra ;
Luo, Zeping ;
Cimermancic, Peter ;
Ule, Jernej ;
Peterlin, B. Matija .
GENES & DEVELOPMENT, 2011, 25 (20) :2158-2172
[8]   ContextMap 2: fast and accurate context-based RNA-seq mapping [J].
Bonfert, Thomas ;
Kirner, Evelyn ;
Csaba, Gergely ;
Zimmer, Ralf ;
Friedel, Caroline C. .
BMC BIOINFORMATICS, 2015, 16
[9]   Perspective Rational Cancer Treatment Combinations: An Urgent Clinical Need [J].
Boshuizen, Julia ;
Peeper, Daniel S. .
MOLECULAR CELL, 2020, 78 (06) :1002-1018
[10]   Transcriptional Addiction in Cancer [J].
Bradner, James E. ;
Hnisz, Denes ;
Young, Richard A. .
CELL, 2017, 168 (04) :629-643