Cell biology. Reversible centriole depletion with an inhibitor of Polo-like kinase 4.
Centrioles are ancient organelles that build centrosomes, the major microtubule-organizing centers of animal cells. Extra centrosomes are a common feature of cancer cells. To investigate the importance of centrosomes in the proliferation of normal and cancer cells, we developed centrinone, a reversible inhibitor of Polo-like kinase 4 (Plk4), a serine-threonine protein kinase that initiates centriole assembly. Centrinone treatment caused centrosome depletion in human and other vertebrate cells. Centrosome loss irreversibly arrested normal cells in a senescence-like G1 state by a p53-dependent mechanism that was independent of DNA damage, stress, Hippo signaling, extended mitotic duration, or segregation errors. In contrast, cancer cell lines with normal or amplified centrosome numbers could proliferate indefinitely after centrosome loss. Upon centrinone washout, each cancer cell line returned to an intrinsic centrosome number "set point." Thus, cells with cancer-associated mutations fundamentally differ from normal cells in their response to centrosome loss.
Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Yao Liang
YL
Wong
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
John V
JV
Anzola
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Robert L
RL
Davis
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Michelle
M
Yoon
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Amir
A
Motamedi
Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Ashley
A
Kroll
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Chanmee P
CP
Seo
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Judy E
JE
Hsia
Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Sun K
SK
Kim
Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Jennifer W
JW
Mitchell
Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.
Brian J
BJ
Mitchell
Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA.
Arshad
A
Desai
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA.
Timothy C
TC
Gahman
Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu.
Andrew K
AK
Shiau
Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu.
Karen
K
Oegema
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002502:Centrioles / Q000187:drug effects*; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D003521:Cyclopropanes; D011720:Pyrazoles
D010879:Piperazines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines; D013450:Sulfones; C000599097:centrinone; C000599098:centrinone-B; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; C490219:PLK4 protein, human