Open AccessDNA polymerase γ inhibition by vitamin K3 induces mitochondria‐mediated cytotoxicity in human cancer cells
Author(s) -
Sasaki Ryohei,
Suzuki Yoko,
Yonezawa Yuko,
Ota Yosuke,
Okamoto Yoshiaki,
Demizu Yusuke,
Huang Peng,
Yoshida Hiromi,
Sugimura Kazuro,
Mizushina Yoshiyuki
Publication year - 2008
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2008.00771.x
Subject(s) - biology , dna damage , cytotoxic t cell , apoptosis , cell growth , cell cycle , dna repair , dna replication , dna polymerase , microbiology and biotechnology , mitochondrion , reactive oxygen species , biochemistry , dna , in vitro
Among the vitamin K (VK) compounds, VK3 exhibits distinct cytotoxic activity in cancer cells and is thought to affect redox cycling; however, the underlying mechanisms remain unclear. Here we demonstrate that VK3 selectively inhibits DNA polymerase (pol) γ, the key enzyme responsible for mitochondrial DNA replication and repair. VK3 at 30 µM inhibited pol γ by more than 80%, caused impairment of mitochondrial DNA replication and repair, and induced a significant increase in reactive oxygen species (ROS), leading to apoptosis. At a lower concentration (3 µM), VK3 did not cause a significant increase in ROS, but was able to effectively inhibit cell proliferation, which could be reversed by supplementing glycolytic substrates. The cytotoxic action of VK3 was independent of p53 tumor suppressor gene status. Interestingly, VK3 only inhibited pol γ but did not affect other pol including human pol α, pol β, pol δ, and pol ɛ. VK1 and VK2 exhibited no inhibitory effect on any of the pol tested. These data together suggest that the inhibition of pol γ by VK3 is relatively specific, and that this compound seems to exert its anticancer activity by two possible mechanisms in a concentration‐dependent manner: (1) induction of ROS‐mediated cell death at high concentrations; and (2) inhibition of cell proliferation at lower concentrations likely through the suppression of mitochondrial respiratory function. These findings may explain various cytotoxic actions induced by VK3, and may pave the way for the further use of VK3. ( Cancer Sci 2008; 99: 1040–1048)