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Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate.

Publication ,  Journal Article
Winter-Vann, AM; Kamen, BA; Bergo, MO; Young, SG; Melnyk, S; James, SJ; Casey, PJ
Published in: Proc Natl Acad Sci U S A
May 27, 2003

The antifolate methotrexate is one of the most successful drugs in cancer chemotherapy. Although its efficacy is widely attributed to a decrease in nucleotide biosynthesis (1), methotrexate is known to increase homocysteine (2), a compound associated with an elevated risk of heart disease, Alzheimer's disease (3), and neural tube defects (4). A potential mechanism for the detrimental effects of homocysteine is cellular hypomethylation from an increase in S-adenosylhomocysteine (5), an inhibitor of methyltransferases including isoprenylcysteine carboxyl methyltransferase (Icmt). Among the substrates of Icmt is the monomeric G protein Ras, a critical component of many signaling pathways that regulate cell growth and differentiation. Because carboxyl methylation of Ras is important for proper plasma membrane localization and function (6), we investigated the role of Icmt in the antiproliferative effect of methotrexate. After methotrexate treatment of DKOB8 cells, Ras methylation is decreased by almost 90%. This hypomethylation is accompanied by a mislocalization of Ras to the cytosol and a 4-fold decrease in the activation of p44 mitogen-activated protein kinase and Akt. Additionally, cells lacking Icmt are highly resistant to methotrexate. Whereas cells expressing wild-type levels of Icmt are inhibited by methotrexate, stable expression of myristoylated H-Ras, which does not require carboxyl methylation for membrane attachment (7), confers resistance to methotrexate. These results suggest that inhibition of Icmt is a critical component of the antiproliferative effect of methotrexate, expanding our understanding of this widely used drug and identifying Icmt as a target for drug discovery.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 27, 2003

Volume

100

Issue

11

Start / End Page

6529 / 6534

Location

United States

Related Subject Headings

  • ras Proteins
  • Signal Transduction
  • S-Adenosylhomocysteine
  • Protein Methyltransferases
  • Mice
  • Methylation
  • Methotrexate
  • Humans
  • Folic Acid Antagonists
  • Animals
 

Citation

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Winter-Vann, A. M., Kamen, B. A., Bergo, M. O., Young, S. G., Melnyk, S., James, S. J., & Casey, P. J. (2003). Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci U S A, 100(11), 6529–6534. https://doi.org/10.1073/pnas.1135239100
Winter-Vann, Ann M., Barton A. Kamen, Martin O. Bergo, Stephen G. Young, Stepan Melnyk, S Jill James, and Patrick J. Casey. “Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate.Proc Natl Acad Sci U S A 100, no. 11 (May 27, 2003): 6529–34. https://doi.org/10.1073/pnas.1135239100.
Winter-Vann AM, Kamen BA, Bergo MO, Young SG, Melnyk S, James SJ, et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6529–34.
Winter-Vann, Ann M., et al. “Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate.Proc Natl Acad Sci U S A, vol. 100, no. 11, May 2003, pp. 6529–34. Pubmed, doi:10.1073/pnas.1135239100.
Winter-Vann AM, Kamen BA, Bergo MO, Young SG, Melnyk S, James SJ, Casey PJ. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc Natl Acad Sci U S A. 2003 May 27;100(11):6529–6534.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

May 27, 2003

Volume

100

Issue

11

Start / End Page

6529 / 6534

Location

United States

Related Subject Headings

  • ras Proteins
  • Signal Transduction
  • S-Adenosylhomocysteine
  • Protein Methyltransferases
  • Mice
  • Methylation
  • Methotrexate
  • Humans
  • Folic Acid Antagonists
  • Animals