Lund University Hompage Översikt Svanborg Leffler Truedsson Undervisning
HAMLET - a folding variant of alpha-lactalbumin from human milk that induces tumor cell death.




Introduction

We have identified a protein complex in the human milk that selectively kills tumor cells and not healthy cells. The complex called HAMLET(Human Alpha-lactalbumin Made LEthal to Tumor cells) consits of partially unfolded alpha-lactalbumin and oleic acid. This complex binds to the cell surface, activates mitochondria and reaches the cell nuclei where it accumulates and interacts with histones. Nuclear uptake occurs exclusively in cells that are sensitive to the tumoricidal activity of hamlet. The tumoricidial activity has also been studied in vivo in gliblastoma, papilloma and bladder cancer models. This group is headed by Ken Mok.

Continued studies aim to:
  • Elucidate the structural basis of HAMLET.
  • Identify cellular targets of the protein, and the difference between tumor cells and healthy cells.
  • Study protection in vivo.



    • Group members

    Aits, Sonja PhD Student sonja.aits@med.lu.se046-2229479
    Lindén, Pontus Technologist pontus.linden@hotmail.com046-2223292
    Lundqvist, Mats MD Student mats.lundqvist.729@student.lu.se 046-2228500
    Mossberg, Anki Technologist, PhD Student Anki.Mossberg@med.lu.se 046-2227185
    Storm, Petter PhD Student petter.storm@med.lu.se046-2228500
    Svanborg, Catharina* Professor Catharina.Svanborg@med.lu.se046-2227185
    Trulsson, Maria PhD Student maria.trulsson@med.lu.se046-2229479
    Westergren, Tomas MD Student tomas.westergren@med.lu.se 046-2228500
    Hou Yuchuan Postdoc Hou.Yu_Chuan@med.lu.se046-2229262
    * Professor Catharina Svanborg is currently on leave of absence and working at the Singapore Immunology Network, A*STAR, Singapore

    Recent articles

    Authors Title Journal Pubmed link
    Aits S, Gustafsson L, Hallgren O, Brest P, Gustafsson M, Trulsson M, Mossberg AK, Simon HU, Mograbi B, Svanborg C. HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death. Int J Cancer. 2009 Mar 1;124(5):1008-19. Pubmed: 19048621
    Hallgren O, Aits S, Brest P, Gustafsson L, Mossberg AK, Wullt B, Svanborg C. Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Adv Exp Med Biol. 2008;606:217-40. Review. Pubmed: 18183931
    Brest P, Gustafsson M, Mossberg AK, Gustafsson L, Duringer C, Hamiche A, Svanborg C. Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET. Cancer Res. 2007 Dec 1;67(23):11327-34. Pubmed: 18056459
    Mossberg AK, Wullt B, Gustafsson L, Mansson W, Ljunggren E, Svanborg C. Bladder cancers respond to intravesical instillation of (HAMLET human alpha-lactalbumin made lethal to tumor cells). Int J Cancer. 2007 Sep 15;121(6):1352-9. Pubmed: 17514650
    Mok KH, Pettersson J, Orrenius S, Svanborg C HAMLET, protein folding, and tumor cell death. Biochem Biophys Res Commun. 2007 Mar 2;354(1):1-7 Pubmed: 17223074
    Pettersson J, Mossberg AK, Svanborg C. alpha-Lactalbumin species variation, HAMLET formation, and tumor cell death. Biochem Biophys Res Commun. 2006 Jun 23;345(1):260-70 Pubmed: 16678133
    Hallgren O, Gustafsson L, Irjala H, Selivanova G, Orrenius S, Svanborg C. HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53. Apoptosis. 2006 Feb;11(2):221-33. Pubmed: 16502260
    Fast J, Mossberg AK, Nilsson H, Svanborg C, Akke M, Linse S. Compact oleic acid in HAMLET. FEBS Lett. 2005 Nov 7;579(27):6095-100. Pubmed: 16229842
    Gustafsson L, Hallgren O, Mossberg AK, Pettersson J, Fischer W, Aronsson A, Svanborg C. HAMLET kills tumor cells by apoptosis: structure, cellular mechanisms, and therapy. J Nutr. 2005 May;135(5):1299-303. Pubmed: 15867328
    Fast J, Mossberg AK, Svanborg C, Linse S. Stability of HAMLET--a kinetically trapped alpha-lactalbumin oleic acid complex. Protein Sci. 2005 Feb;14(2):329-40. Pubmed: 15659367
    Gustafsson L, Leijonhufvud I, Aronsson A, Mossberg AK, Svanborg C. Treatment of skin papillomas with topical alpha-lactalbumin-oleic acid. N Engl J Med. 2004 Jun 24;350(26):2663-72. Pubmed: 15215482
    Baltzer A, Svanborg C, Jaggi R. Apoptotic cell death in the lactating mammary gland is enhanced by a folding variant of alpha-lactalbumin. Mol Life Sci. 2004 May;61(10):1221-8. Pubmed: 15141307
    Casbarra A, Birolo L, Infusini G, Dal Piaz F, Svensson M, Pucci P, Svanborg C, Marino G. Conformational analysis of HAMLET, the folding variant of human alpha-lactalbumin associated with apoptosis. Protein Sci. 2004 May;13(5):1322-30 Pubmed: 15075403
    Fischer W, Gustafsson L, Mossberg AK, Gronli J, Mork S, Bjerkvig R, Svanborg C. Human alpha-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res. 2004 Mar 15;64(6):2105-12. Pubmed: 15026350
    Svensson M, Mossberg AK, Pettersson J, Linse S, Svanborg C. Lipids as cofactors in protein folding: stereo-specific lipid-protein interactions are required to form HAMLET (human alpha-lactalbumin made lethal to tumor cells). Protein Sci. 2003 Dec;12(12):2805-14. Pubmed: 14627740
    Svensson M, Fast J, Mossberg AK, Duringer C, Gustafsson L, Hallgren O, Brooks CL, Berliner L, Linse S, Svanborg C. Alpha-lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human alpha-lactalbumin made lethal to tumor cells). Protein Sci. 2003 Dec;12(12):2794-804. Pubmed: 14627739
    Duringer C, Hamiche A, Gustafsson L, Kimura H, Svanborg C. HAMLET interacts with histones and chromatin in tumor cell nuclei. J Biol Chem. 2003 Oct 24;278(43):42131-5. Pubmed: 12888554
    Svanborg C, Agerstam H, Aronson A, Bjerkvig R, Duringer C, Fischer W, Gustafsson L, Hallgren O, Leijonhuvud I, Linse S, Mossberg AK, Nilsson H, Pettersson J, Svensson M. HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects. Adv Cancer Res. 2003;88:1-29. Pubmed: 12665051
    Svensson M, Duringer C, Hallgren O, Mossberg AK, Hakansson A, Linse S, Svanborg C. Hamlet--a complex from human milk that induces apoptosis in tumor cells but spares healthy cells. Adv Exp Med Biol. 2002;503:125-32. Pubmed: 12026011
    Kohler C, Gogvadze V, Hakansson A, Svanborg C, Orrenius S, Zhivotovsky B. Abstract A folding variant of human alpha-lactalbumin induces mitochondrial permeability transition in isolated mitochondria. Eur J Biochem. 2001 Jan;268(1):186-91. Pubmed: 11121120
    Svensson M, Hakansson A, Mossberg AK, Linse S, Svanborg C. Conversion of alpha-lactalbumin to a protein inducing apoptosis. Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4221-6. Pubmed: 10760289