Carcinogenesis, Vol 19, 1467-1474, Copyright © 1998 by Oxford University Press
J Przybyszewski, HC Box and M Kulesz-Martin
Evidence for the involvement of oxidative stress in 12-O-
tetradecanoylphorbol-13-acetate (TPA)-mediated tumor promotion has focused
on non-initiated immune cells, tumor cell lines and non- initiated
epidermis treated in vivo. This paper reports the effects of TPA on
8-hydroxydeoxyguanosine (8OHdG) formation and the generation of reactive
oxygen species (ROS) in cloned initiated mouse epidermal keratinocytes in
order to determine whether TPA can directly damage DNA through ROS
production within the keratinocytes. Using high performance liquid
chromatography with electrochemical detection (HPLC-EC), TPA did not induce
8OHdG formation in DNA of initiated keratinocytes treated under a variety
of conditions. The reliability of the HPLC-EC system is demonstrated by (i)
the linearity of the 8OHdG standard curve; (ii) the consistency of 8OHdG
measurements in calf thymus and cellular DNA; and (iii) the dose-dependent
increase in 8OHdG in DNA of initiated keratinocytes treated with UVC in the
presence and absence of H2O2. Though not DNA-damaging, TPA induced a 65%
increase in ROS (P < 0.05) as detected by luminol-dependent
chemiluminescence. These results support a mechanism for the role of
oxidative stress in tumor promotion that does not involve direct DNA damage
to the keratinocyte target cell. The relationship between ROS, signal
transduction and tumor promotion is discussed in light of the above results
which is consistent with the role of TPA-induced ROS as second messengers
in signal transduction.
ARTICLES
Induction of reactive oxygen species without 8-hydroxydeoxyguanosine formation in DNA of initiated mouse keratinocytes treated with 12-O- tetradecanoylphorbol-13-acetate [published erratum appears in Carcinogenesis 1998 Nov;19(11):2059]
Biophysics Department, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. przybysz1@com.msu.edu
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