A chemosensitization screen identifies TP53RK, a kinase that restrains apoptosis after mitotic stress.

Taxanes are very effective at causing mitotic arrest; however, there is variability among cancer cells in the apoptotic response to mitotic arrest. The variability in clinical efficacy of taxane-based therapy is likely a reflection of this variability in apoptotic response, thus elucidation of the molecular mechanism of the apoptotic response to mitotic stress could lead to improved clinical strategies. To identify genes whose expression influences the rate and extent of apoptosis after mitotic arrest, we screened a kinase-enriched small interfering RNA library for effects on caspase activation in response to maximally effective doses of paclitaxel, a PLK1 inhibitor, or cisplatin. Small interfering RNA oligonucleotides directed against an atypical protein kinase, TP53RK, caused the greatest increase in caspase-3/7 activation in response to antimitotic agents. Time-lapse microscopy revealed that cells entered mitosis with normal kinetics, but died after entry into mitosis in the presence of paclitaxel more rapidly when TP53RK was depleted. Because expression levels of TP53RK vary in cancers, TP53RK levels could provide a molecular marker to predict response to antimitotic agents. TP53RK inhibition may also sensitize cancers to taxanes.

• Publication year

  2010

• Venue

  Cancer Research

• Publication date

  2010-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1158/0008-5472.CAN-10-0015PMID 20647325
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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