Therapeutics by Cytotoxic Metabolite Accumulation: Pemetrexed Causes ZMP Accumulation, AMPK Activation, and Mammalian Target of Rapamycin Inhibition
Open Access
- 1 July 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 69 (13), 5467-5474
- https://doi.org/10.1158/0008-5472.can-08-4979
Abstract
Pemetrexed represents the first antifolate cancer drug to be approved by the Food and Drug Administration in 20 years; it is currently in widespread use for first line therapy of mesothelioma and non–small cell lung cancer. Pemetrexed has more than one site of action; the primary site is thymidylate synthase. We now report that the secondary target is the downstream folate-dependent enzyme in de novo purine synthesis, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). The substrate of the AICART reaction, ZMP, accumulated in intact pemetrexed-inhibited tumor cells, identifying AICART as the step in purine synthesis that becomes rate-limiting after drug treatment. The accumulating ZMP causes an activation of AMP-activated protein kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and hypophosphorylation of the downstream targets of mTOR that control initiation of protein synthesis and cell growth. We suggest that the activity of pemetrexed against human cancers is a reflection of its direct inhibition of folate-dependent target proteins combined with prolonged inhibition of the mTOR pathway secondary to accumulation of ZMP. [Cancer Res 2009;69(13):5467–74]Keywords
This publication has 38 references indexed in Scilit:
- AMPK Phosphorylation of Raptor Mediates a Metabolic CheckpointMolecular Cell, 2008
- AMP-activated/SNF1 protein kinases: conserved guardians of cellular energyNature Reviews Molecular Cell Biology, 2007
- Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applicationsMolecular Cancer Therapeutics, 2007
- Upstream of the mammalian target of rapamycin: do all roads pass through mTOR?Oncogene, 2006
- Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide ribosideMolecular Cancer Therapeutics, 2006
- The inverse relationship between reduced folate carrier function and Pemetrexed activity in a human colon cancer cell lineMolecular Cancer Therapeutics, 2006
- EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinibProceedings of the National Academy of Sciences of the United States of America, 2004
- Role of AMP-activated protein kinase in mechanism of metformin actionJCI Insight, 2001
- 5′‐AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP‐activated protein kinase. Studies using bacterially expressed human protein phosphatase‐2Cα and native bovine protein phosphatase‐2AcFEBS Letters, 1995
- Feedback Control of Purine Biosynthesis by Purine RibonucleotidesNature, 1959