Lysophosphatidic acid production and action: Validated targets in cancer?

Makiko Umezu-Goto, Janos Tanyi, John Lahad, Shuying Liu, Shuangxing Yu, Ruth Lapushin, Yutaka Hasegawa, Yiling Lu, Rosanne Trost, Therese Bevers, Eric Jonasch, Ken Aldape, Jinsong Liu, Robyn D. James, Colin G. Ferguson, Yong Xu, Glenn D. Prestwich, Gordon B. Mills

    Research output: Contribution to journalArticle

    75 Scopus citations

    Abstract

    The completion of the human genome project, the evolution of transcriptional profiling and the emergence of proteomics have focused attention on these areas in the pathophysiology and therapy of cancer. The role of lysophospholipids as potential mediators in cancer pathophysiology, screening and management has taken a major leap forward with the recent cloning of several enzymes involved in the metabolism of lysophospholipids. Lysophospholipids, although small molecules, contain a high "informational" content. Differences include the nature of the phosphate head group, the regiochemistry of the fatty acyl chain on the glyceryl backbone, the presence of ether versus ester linkages to the backbone, and the length and saturation of the fatty acyl or alkyl chain. This informational content is sufficient to result in a marked structure function activity relationship at their cognate receptors. Thus the emerging discipline of "functional lipidomics" is likely to prove as important as genomics and proteomics in terms of early diagnosis, prognosis, and therapy. Lysophospholipid levels are elevated in vivo in a number of pathophysiological states including ascitic fluid from ovarian cancer patients indicating a role in the pathophysiology of this devastating disease. Although controversial, levels of specific lysophospholipids may be altered in the blood of cancer patients providing a potential mechanism for early diagnosis. Several of the enzymes involved in the metabolism of lysophospholipids are aberrant in ovarian and other cancers. Further, the enzymes are active in the interstitial space, rendering them readily accessible to the effects of inhibitors including antibodies, proteins, and small molecules. In support of a role for lysophospholipids in the pathophysiology of cancer, expression of receptors for lysophospholipids is also aberrant in cancer cells from multiple different lineages. All of the cell surface receptors for lysophospholipids belong to the G protein coupled receptor family. As over 40% of all drugs in current use target this family of receptors, lysophospholipid receptors are highly "druggable." Indeed, a number of highly specific agonists and antagonists of lysophospholipid receptors have been identified. A number are in preclinical evaluation as therapeutics. We look forward to the next several years when the role of lysophospholipids in physiology and the pathophysiology and management of cancer and other diseases are fully elucidated.

    Original languageEnglish (US)
    Pages (from-to)1115-1140
    Number of pages26
    JournalJournal of cellular biochemistry
    Volume92
    Issue number6
    DOIs
    StatePublished - 2004

    Keywords

    • Autotaxin
    • Cancer
    • Lysophosphatidic acid
    • Treatment

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology
    • Cell Biology

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  • Cite this

    Umezu-Goto, M., Tanyi, J., Lahad, J., Liu, S., Yu, S., Lapushin, R., Hasegawa, Y., Lu, Y., Trost, R., Bevers, T., Jonasch, E., Aldape, K., Liu, J., James, R. D., Ferguson, C. G., Xu, Y., Prestwich, G. D., & Mills, G. B. (2004). Lysophosphatidic acid production and action: Validated targets in cancer? Journal of cellular biochemistry, 92(6), 1115-1140. https://doi.org/10.1002/jcb.20113