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).

Abstract

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.

• Authors: T Ishikawa, K Akimaru, M Nakanishi, K Tomokiyo, K Furuta, M Suzuki, R Noyori
• Journal: The Biochemical journal (Biochem J) Vol. 336 ( Pt 3) Pg. 569-76 (Dec 15 1998) ISSN: 0264-6021 [Print] England
• PMID: 9841867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• CDKN1A protein, human
• Carrier Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Enzyme Inhibitors
• Growth Inhibitors
• Membrane Transport Proteins
• Prostaglandins A, Synthetic
• RNA, Messenger
• glutathione transporter
• Adenosine Triphosphate
• 9-oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester

Topics

• Adenosine Triphosphate (metabolism)
• Antineoplastic Agents (pharmacology)
• Carrier Proteins (antagonists & inhibitors)
• Cell Cycle
• Cell Division (drug effects)
• Cell Membrane (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (genetics, pharmacology)
• Enzyme Inhibitors (pharmacology)
• Gene Expression
• Genes, myc
• Growth Inhibitors (pharmacology)
• HL-60 Cells
• Humans
• Membrane Transport Proteins
• Prostaglandins A, Synthetic (pharmacology)
• RNA, Messenger (metabolism)