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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 265-274
Myeloma Cells Selected for Resistance to CD95-Mediated Apoptosis
Are Not Cross-Resistant to Cytotoxic Drugs: Evidence for Independent
Mechanisms of Caspase Activation
Terry H. Landowski,
Kenneth H. Shain,
Marc M. Oshiro,
Ibrahim Buyuksal,
Jeffrey S. Painter, and
William S. Dalton
We have previously shown that selection for resistance to the
anthracenes, doxorubicin or mitoxantrone, results in coselection for
resistance to CD95-mediated apoptosis (Landowski et al: Blood 89:1854, 1997). In the present study, we were interested in determining if the converse is also true; that is, does selection for CD95 resistance coselect for resistance to chemotherapeutic drugs. To
address this question, we used two isogenic models of CD95-resistant versus CD95-sensitive cell lines: 8226/S myeloma cells selected for
resistance to CD95-mediated apoptosis; and K562 cells expressing ectopic CD95. Repeated exposure of the CD95-sensitive human myeloma cell line, 8226/S, to agonistic anti-CD95 antibody resulted in a cell
line devoid of CD95 receptor surface expression and completely resistant to CD95-mediated apoptosis. Multiple clonal populations derived from the CD95-resistant cell line showed no difference in
sensitivity to doxorubicin, mitoxantrone, Ara-C, or etoposide, demonstrating that cross-resistance between Fas-mediated apoptosis and
drug-induced apoptosis occurs only when cytotoxic drugs are used as the
selecting agent. Using the inverse approach, we transfected the
CD95-negative cell line, K562, with a CD95 expression vector. Clones
expressing variable levels of cell-surface CD95 were isolated by
limiting dilution, and analyzed for sensitivity to CD95-mediated apoptosis and response to chemotherapeutic drugs. We show that CD95
surface expression confers sensitivity to CD95-mediated apoptosis; however, it does not alter response to chemotherapeutic drugs. Similarly, doxorubicin-induced activation of caspases 3 and 8 was
identical in the CD95-sensitive and CD95-resistant cell lines in both
isogenic cell systems. In addition, prior treatment with the CD95
receptor-blocking antibody, ZB4, inhibited CD95-activated apoptosis in
8226/S cells, but had no effect on doxorubicin cytotoxicity. These
results show that CD95 and chemotherapeutic drugs use common apoptotic
effectors, but the point of convergence in these two pathways is
downstream of CD95 receptor/ligand interaction.
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