PROLIFERATION-DEPENDENT VS INDEPENDENT PROGRAMMED CELL-DEATH OF PROSTATIC-CANCER CELLS INVOLVES DISTINCT GENE-REGULATION

Androgen-independent Dunning R-3327 AT-3 rat prostatic cancer cells ca n be induced to undergo programmed cell death in either a proliferatio n-dependent or independent manner depending upon the therapeutic agent used. In the present study, 5-fluorodeoxyuridine (5-FrdU) was used to induce proliferation-dependent death of the AT-3 cells via its abilit y to inhibit thymidylate synthetase. Ionomycin and thapsigargin were u sed to induce proliferation-independent death of these cells via their ability to sustain an elevation in intracellular free Ca2+. Based upo n the temporal sequence of DNA fragmentation, morphologic changes, and loss of cell viability, each of the three test agents, at the doses u sed, induces the programmed death of AT-3 cells with essentially ident ical kinetics. Based upon these similarities, comparisons of the patte rn of gene expression during the proliferation-dependent (i.e., 5-FrdU -induced) vs. proliferation-independent (i.e., ionomycin and thapsigar gin-induced) programmed death of AT-3 cells allow identification of ge nes whose enhanced expression is involved in the initiation vs. comple tion of programmed cell death. Based upon this approach, enhanced H-ra s and TRPM-2 expression is associated with initiation of proliferation -dependent programmed death of AT-3 cells while enhanced c-myc, calmod ulin, and alpha-prothymosin expression is associated with initiation o f proliferation-independent programmed death of these cells. In contra st, enhanced expression of glucose-regulated 78 kilodalton and tissue transglutaminase genes are associated with the completion of programme d cell death, since their expression is enhanced in both proliferation -dependent and independent programmed cell death of AT-3 cells. (C) 19 94 Wiley-Liss, Inc.