Md. Ruiz-ruiz et A. Lopez-rivas, p53-mediated up-regulation of CD95 is not involved in genotoxic drug-induced apoptosis of human breast tumor cells, CELL DEAT D, 6(3), 1999, pp. 271-280
Induction of CD95 (Fas/APO-1) and CD95 ligand during chemotherapeutic treat
ment may contribute to the death by apoptosis of some tumor cells, In this
study, we have analyzed the role of the CD95 system in genotoxic drug-induc
ed death of human breast tumor cells, Incubation of the breast tumor cell l
ines MCF-7 and EVSA-T with doxorubicin or methotrexate caused apoptosis aft
er 48 h of treatment, These drugs induced a marked increase in the level of
CD95 mRNA and protein in wild-type p53-expressing MCF-7 cells. On the cont
rary, the breast cancer cell line EVSA-T that expresses high levels of an i
nactive form of p53, did not up-regulate CD95 upon drug treatment. Elevatio
n of CD95 expression by DNA-damaging drugs was notably blocked in MCF-7 cel
ls expressing the human papillomavirus type 16 E6 protein (E6 cells) which
prevented p53 accumulation upon DNA damage, However, E6 cells were still ki
lled by the drugs. Furthermore, the genotoxic drugs did not induce the expr
ession of CD95 ligand in MCF-7 cells at doses that caused apoptosis in thes
e breast tumor cells. Moreover, drug-induced apoptosis of breast tumor cell
s was not prevented in the presence of either a CD95 antagonistic antibody
or a CD95 ligand blocking antibody. We also observed a strong synergism bet
ween lower doses of DNA-damaging drugs and CD95 agonistic antibody in the i
nduction of apoptosis in MCF-7 cells. In summary, our data indicate that dr
ug-induced apoptosis of breast tumor cells occurs by a CD95/CD95L-independe
nt mechanism although by elevating the tumor suppressor proteins p53 and CD
95, genotoxic drugs may sensitize breast tumor cells to CD95-mediated apopt
osis.