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.
Peterson
David
D
Research Oncology, Genentech, Inc., South San Francisco, California, USA.
Lee
James
J
Lei
Xingye C
XC
Forrest
William F
WF
Davis
David P
DP
Jackson
Peter K
PK
Belmont
Lisa D
LD
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C441644:TP53RK protein, human; D017239:Paclitaxel; D002945:Cisplatin