Anti-cancer-prostaglandin-induced cell-cycle arrest and its modulation by an inhibitor of the ATP-dependent glutathione S-conjugate export pump (GS-X pump).
The A and J series of prostaglandins (PGs) accumulate in the nuclei to suppress the proliferation of cancer cells. Here we report that Delta7-PGA1 methyl ester, a synthetic anti-cancer PG, increased the level of mRNA for the cyclin-dependent kinase inhibitor p21 in human leukaemia HL-60 cells. The induction of p21 was associated with the accumulation of hypophosphorylated retinoblastoma protein (pRB) and the suppression of c-myc gene expression. Since the p53 gene is deleted in HL-60 cells, the anti-cancer PG is suggested to inhibit cancer cell growth by inducing p21 via a p53-independent pathway. Unlike HL-60 cells, cisplatin-resistant HL-60/R-CP cells were insensitive to Delta7-PGA1 methyl ester. While c-myc expression was transiently suppressed, neither G1 arrest nor hypophosphorylation of pRB was observed with the anti-cancer PG. Plasma membrane vesicles from HL-60/R-CP cells showed an enhanced level of GS-X pump (ATP-dependent glutathione S-conjugate export pump) activity towards the glutathione S-conjugate of Delta7-PGA1 methyl ester (Km 110 nM). GIF-0019 ¿N-carbomethoxy-S-[5-(4-benzoylphenyl)pentyl]glutathione dimethyl ester¿, a specific inhibitor of the GS-X pump, dose-dependently enhanced the cellular sensitivity of HL-60/R-CP cells to Delta7-PGA1 methyl ester and induced G1 arrest. The GS-X pump is suggested to play a pivotal role in modulating the biological action of the anti-cancer PG.
Ishikawa
T
T
Section of Molecular Therapeutics, Department of Experimental Pediatrics The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Akimaru
K
K
Nakanishi
M
M
Tomokiyo
K
K
Furuta
K
K
Suzuki
M
M
Noyori
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D016259:Genes, myc; D006131:Growth Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D026901:Membrane Transport Proteins; D011455:Prostaglandins A, Synthetic / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D026901:Membrane Transport Proteins; D011455:Prostaglandins A, Synthetic; D012333:RNA, Messenger; C086860:glutathione transporter; D000255:Adenosine Triphosphate; C048481:9-oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester