Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index.
Dysregulated cellular proliferation is a characteristic property of cancer. We show that, despite this fact, cancers maintain high amplitude, circadian rhythms in their growth, DNA synthesis, and mitosis. These patterns are accompanied by the daily traverse of BMAL-1 protein between the cytoplasm, where it is produced, and nucleus, where it influences timing of cancer cell proliferation. This core clock gene product gates cancer cell proliferation by coordinating clock-controlled proteins, thymidylate synthase [thymidylate synthase activity (TSA) cell DNA replication], WEE-1 (cell mitosis), and vascular endothelial growth factor (growth). 5-Fluorouracil (5-FU)-induced host bone marrow and gut toxicity and tumor shrinkage following administration at six equispaced times of day allowed determination of circadian relationships among tumor growth, relevant clock, and clock-controlled proteins and dependence of 5-FU target availability (TSA) in normal and cancer tissues and resultant 5-FU toxic-therapeutic index. The time of day (hours after lights on) of low TSA in each tissue and tumor is respectively associated with greatest toxicity to that tissue and greatest tumor shrinkage. 5-FU treatment near daily awakening results in least damage to bone marrow and gut, greatest antitumor effect, and best survival. This time of day is associated with maximum tumor nuclear BMAL-1 and total cell WEE-1 protein. The described chain of events, for the first time, links cancer cell clock proteins, cancer cell DNA synthesis, proliferation, TSA, and 5-FU toxic-therapeutic index, explaining the dependence of cancer outcome on circadian timing of 5-FU.
Wood
Patricia A
PA
William Jennings Bryan Dorn Veterans Affairs Medical Center, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, 29209, USA.
Du-Quiton
Jovelyn
J
You
Shaojin
S
Hrushesky
William J M
WJ
D056930:ARNTL Transcription Factors; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D008940:Mitotic Index; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D013940:Thymidylate Synthase / Q000187:drug effects / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D056930:ARNTL Transcription Factors; D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D018797:Cell Cycle Proteins; D005472:Fluorouracil; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D013940:Thymidylate Synthase; D042461:Vascular Endothelial Growth Factor A; C538961:Bmal1 protein, mouse; C499348:Wee1 protein, mouse