Antitumor Complexes Formed by Oleic Acid and Molten Globule Intermediates of Proteins

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Abstract

Human α-lactalbumin made lethal to tumor cells (HAMLET), a complex formed by human α-lactalbumin and oleic acid, has a unique apoptotic activity for the selective killing of tumor cells. It has been hypothesized that HAMLET expresses its antitumor activity in the stomach of breast-fed infants, thereby protecting the infants from tumor development, and in this case the protein portion of HAMLET is in a flexible molten globule state. On the other hand, the primary biological function of α-lactalbumin in its rigid native structure is to modify the specificity of galactosyltransferase to produce lactose in mammary glands. α-Lactalbumin thus provides a unique example, in which a single globular protein has two independent biological functions in quite different locations. In this article, we summarize the historical background and recent progress of the studies on HAMLET and related protein-fatty acid complexes. It is shown that oleic acid forms an antitumor complex not only with α-lactalbumin but also with various globular proteins in the molten globule state by nonspecific hydrophobic interactions, although the strength of the activity varies somewhat depending on the protein species. Similarly, not only oleic acid but also various cytotoxic fatty acids (mono- and polyunsaturated cis fatty acids) are bound to α-lactalbumin in the molten globule state and exhibit the antitumor activities. It is thus concluded that the protein portion of these complexes is not the origin of their cytotoxicity but plays a role as the delivery carrier of cytotoxic fatty acid molecules into tumor cells across the cell membrane.

Keywords

HAMLET α-Lactalbumin NMR Molten globule Oleic acid Antitumor complex Apoptosis 
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Notes

Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant number 23107725) and by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (grant number 25440075).

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Copyright information

© Springer Japan 2016

Authors and Affiliations

  1. 1.Okazaki Institute for Integrative Bioscience and Institute for Molecular ScienceOkazakiJapan
  2. 2.Department of Functional Molecular ScienceSchool of Physical Sciences, The Graduate University for Advanced Studies (Sokendai)OkazakiJapan
  3. 3.The Center for the Promotion of Integrated SciencesThe Graduate University for Advanced Studies (Sokendai)HayamaJapan
  4. 4.School of Computational SciencesKorea Institute for Advanced Study (KIAS)SeoulSouth Korea
  5. 5.Department of PhysicsSchool of Science, University of TokyoTokyoJapan
  6. 6.Fuji Pharma Co., Ltd.TokyoJapan

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