Ea. Rorke et al., POLYCYCLIC AROMATIC-HYDROCARBONS ENHANCE TERMINAL CELL-DEATH OF HUMANECTOCERVICAL CELLS, International journal of oncology, 13(3), 1998, pp. 557-563
Polycyclic aromatic hydrocarbons (PAH) are a class of chemical carcino
gens whose active metabolites form DNA adducts, resulting in specific
mutational events. The tumor suppressor protein p53 is believed to pla
y a pivotal role in the ability of cells to response to DNA damage, re
sulting in either cell cycle arrest in G(1) or apoptosis under conditi
ons Of excessive damage This growth inhibition it is associated with t
he concomitant induction of p53 and enhanced terminal cell differentia
tion. In this study we evaluated the effects of PAH on cell growth, ce
ll differentiation, xenobiotic metabolism, and DNA adduct levels in no
rmal ectocervical epithelial cells (ECE) and compared them to cervical
cells whose p53 have been inactivated either by binding to viral HPV
E6 oncogene (ECE16-1) or by mutation (C33A). The PAH 3-methylcholanthr
ene (3MC) inhibited normal ECE and to a lesser extent ECE16-1 cell pro
liferation. Not only did the growth inhibition occur at lower concentr
ations in the normal cells but the extent of inhibition was also great
er in normal as compared to immortalized cells. Benzanthracene (BA) ha
d a minor effect on normal ECE cells with no effect on immortalized EC
E16-1 cells. C33A cell growth was unaffected by 3MC and BA. Terminal c
ell death was enhanced only in normal ECE cells as evidenced by increa
sed envelope formation and was paralleled by an increase in the level
of p53 following 3MC treatment. The differentiation status of the 3MC-
treated cells was similar to untreated cells as indicated by three ind
ependent markers of cell differentiation; transglutaminase, involucrin
, keratin expression. There was no difference in the pattern or level
of DNA adducts formed in normal and immortalized cells following 3MC t
reatment. In addition the basal level of metabolism of C-14-BaP to phe
nols, diols and quinnones was unaltered by pretreatment with either 3M
C or BA. These results demonstrate that immortalized cervical cells ar
e less sensitive to toxicant damage [i.e. cell proliferation and termi
nal differentiation], and as a result, immortalized cells proliferate
in the presence of genotoxic damage and are at increased risk for muta
tions and cancer.