Prostaglandin J2 and 15-deoxy-delta12,14-prostaglandin J2 induce proliferation of cyclooxygenase-depleted colorectal cancer cells.
Increased expression of cyclooxygenase (COX) and overproduction of prostaglandins (PGs) have been implicated in the development and progression of colorectal cancer (CRC). Nonsteroidal anti-inflammatory agents (NSAIDS) inhibit growth of various CRC cell lines by both COX-dependent and COX-independent pathways. To specifically examine the effect of COX and PGs on proliferation in CRC cells, we introduced an antisense COX-2 cDNA construct under the control of a tetracycline (Tc)-inducible promoter into a CRC cell line, HCA-7, Colony 29 (HCA-7) that expresses COX and produces PGs. In the presence of Tc, PG production in COX-depleted cells was reduced 99.8% compared with either uninduced transfectants or parental HCA-7 cells. This decrease in PG production was associated with a concomitant 60% reduction in DNA replication. Subsequently, we examined the effects of various PGs to modulate cell growth in COX-depleted HCA-7 or COX-null HCT-15 cells by quantifying [3H]thymidine incorporation and/or growth in collagen gels. We report that J-series cyclopentenone PGs, particularly PGJ2 and 15-deoxy-delta12,14-PGJ2, induce proliferation of these cells at nanomolar concentrations. Lipids extracted from parental HCA-7 cell conditioned medium stimulated mitogenesis in COX-depleted HCA-7 cells and COX-null HCT-15 cells. Using chromatographic and mass spectrometric approaches, we were able to detect PGJ2 in conditioned medium from parental HCA-7 cells. Taken together, these findings implicate a role for cyclopentenone PGs in CRC cell proliferation.
Chinery
R
R
Department of Medicine, and The Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Coffey
R J
RJ
Graves-Deal
R
R
Kirkland
S C
SC
Sanchez
S C
SC
Zackert
W E
WE
Oates
J A
JA
Morrow
J D
JD
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D051546:Cyclooxygenase 2; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency* / Q000378:metabolism; D008055:Lipids / Q000494:pharmacology; D008565:Membrane Proteins; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency* / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000900:Anti-Bacterial Agents; D007527:Isoenzymes; D008055:Lipids; D008565:Membrane Proteins; D011453:Prostaglandins; C037112:9-deoxy-delta-9-prostaglandin D2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013752:Tetracycline; D015230:Prostaglandin D2