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Future Oncology Volume 8, 2012 - Issue 10
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Review

HAMLET: Functional Properties and Therapeutic Potential

James Ho CS1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
,
Anna Rydström1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
,
Maria Trulsson1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
,
Johannes Bålfors1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
,
Petter Storm1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
,
Manoj Puthia1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
,
Aftab Nadeem1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]View further author information
&
Catharina Svanborg1 Department of Microbiology, Immunology & Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Sölvegatan 23, S-223 62Lund, Sweden. [email protected]Correspondence[email protected]
View further author information
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Pages 1301-1313 | Published online: 06 Nov 2012

References

  • Hanahan D , WeinbergRA. The hallmarks of cancer.Cell100(1), 57–70 (2000).
  • Hanahan D , WeinbergRA. Hallmarks of cancer: the next generation.Cell144(5), 646–674 (2011).
  • Argiris K , PanethymitakiC, TavassoliM. Naturally occurring, tumor-specific, therapeutic proteins.Exp. Biol Med. (Maywood)236(5), 524–536 (2011).
  • Berge E , ThompsonC, MessersmithW. Development of novel targeted agents in the treatment of metastatic colorectal cancer.Clin. Colorectal Cancer10(4), 266–278 (2011).
  • Flaherty KT , HodiFS, FisherDE. From genes to drugs: targeted strategies for melanoma.Nat. Rev. Cancer12(5), 349–361 (2012).
  • Fu Y , ZhengS, AnNet al. β-catenin as a potential key target for tumor suppression. Int. J. Cancer 129(7), 1541–1551 (2011).
  • Los M , PanigrahiS, RashediIet al. Apoptin, a tumor-selective killer. Biochim. Biophys. Acta 1793(8), 1335–1342 (2009).
  • Sethi N , KangY. Unravelling the complexity of metastasis – molecular understanding and targeted therapies.Nat. Rev. Cancer11(10), 735–748 (2011).
  • Hakansson A , ZhivotovskyB, OrreniusS, SabharwalH, SvanborgC. Apoptosis induced by a human milk protein.Proc. Natl Acad. Sci. USA92(17), 8064–8068 (1995).
  • Svensson M , HakanssonA, MossbergAK, LinseS, SvanborgC. Conversion of α-lactalbumin to a protein inducing apoptosis.Proc. Natl Acad. Sci. USA97(8), 4221–4226 (2000).
  • Svanborg C , AgerstamH, AronsonAet al. HAMLET kills tumor cells by an apoptosis-like mechanism – cellular, molecular, and therapeutic aspects. Adv. Cancer Res. 88, 1–29 (2003).
  • Storm P , AitsS, PuthiaMKet al. Conserved features of cancer cells define their sensitivity to HAMLET-induced death; c-Myc and glycolysis. Oncogene 30(48), 4765–4779 (2011).
  • Fischer W , GustafssonL, MossbergAKet al. Human α-lactalbumin made lethal to tumor cells (HAMLET) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival. Cancer Res. 64(6), 2105–2112 (2004).
  • Gustafsson L , LeijonhufvudI, AronssonA, MossbergAK, SvanborgC. Treatment of skin papillomas with topical α-lactalbumin-oleic acid.N. Engl. J. Med.350(26), 2663–2672 (2004).
  • Mossberg AK , WulltB, GustafssonL, ManssonW, LjunggrenE, SvanborgC. Bladder cancers respond to intravesical instillation of HAMLET (human α-lactalbumin made lethal to tumor cells).Int. J. Cancer121(6), 1352–1359 (2007).
  • Beadle GW , TatumEL. Genetic control of biochemical reactions in neurospora.Proc. Natl Acad. Sci. USA27(11), 499–506 (1941).
  • Valdivia HH . One gene, many proteins: alternative splicing of the ryanodine receptor gene adds novel functions to an already complex channel protein.Circ. Res.100(6), 761–763 (2007).
  • Venter JC . Genome-sequencing anniversary. The human genome at 10: successes and challenges.Science331(6017), 546–547 (2011).
  • Venter JC , AdamsMD, MyersEWet al. The sequence of the human genome. Science 291(5507), 1304–1351 (2001).
  • Pettersson-Kastberg J , AitsS, GustafssonLet al. Can misfolded proteins be beneficial? The HAMLET case. Ann. Med. 41(3), 162–176 (2009).
  • Jeffery CJ . Moonlighting proteins.Trends Biochem. Sci.24(1), 8–11 (1999).
  • Jeffery CJ . Multifunctional proteins: examples of gene sharing.Ann. Med.35(1), 28–35 (2003).
  • Jeffery CJ . Moonlighting proteins – an update.Mol. Biosyst.5(4), 345–350 (2009).
  • Dyson HJ , WrightPE. Intrinsically unstructured proteins and their functions.Nat. Rev. Mol. Cell Biol.6(3), 197–208 (2005).
  • Soto C . Transmissible proteins: expanding the prion heresy.Cell149(5), 968–977 (2012).
  • Svensson M , SabharwalH, HakanssonAet al. Molecular characterization of α-lactalbumin folding variants that induce apoptosis in tumor cells. J. Biol. Chem. 274(10), 6388–6396 (1999).
  • Kuwajima K . The molten globule state of α-lactalbumin.FASEB J.10(1), 102–109 (1996).
  • Mok KH , NagashimaT, DayIJ, HorePJ, DobsonCM. Multiple subsets of side-chain packing in partially folded states of α-lactalbumins.Proc. Natl Acad. Sci. USA102(25), 8899–8904 (2005).
  • Peng ZY , KimPS. A protein dissection study of a molten globule.Biochemistry33(8), 2136–2141 (1994).
  • Chyan CL , WormaldC, DobsonCM, EvansPA, BaumJ. Structure and stability of the molten globule state of guinea-pig α-lactalbumin: a hydrogen exchange study.Biochemistry32(21), 5681–5691 (1993).
  • Schulman BA , RedfieldC, PengZY, DobsonCM, KimPS. Different subdomains are most protected from hydrogen exchange in the molten globule and native states of human α-lactalbumin.J. Mol. Biol.253(5), 651–657 (1995).
  • Polverino De Laureto P , FrareE, GottardoR, FontanaA. Molten globule of bovine α-lactalbumin at neutral pH induced by heat, trifluoroethanol, and oleic acid: a comparative analysis by circular dichroism spectroscopy and limited proteolysis. Proteins 49(3), 385–397 (2002).
  • Wu LC , PengZY, KimPS. Bipartite structure of the α-lactalbumin molten globule.Nat. Struct. Biol.2(4), 281–286 (1995).
  • Acharya KR , RenJS, StuartDI, PhillipsDC, FennaRE. Crystal structure of human α-lactalbumin at 1.7 A resolution.J. Mol. Biol.221(2), 571–581 (1991).
  • Vanaman TC , BrewK, HillRL. The disulfide bonds of bovine α-lactalbumin.J. Biol. Chem.245(17), 4583–4590 (1970).
  • Hiraoka Y , SegawaT, KuwajimaK, SugaiS, MuraiN. α-lactalbumin: a calcium metalloprotein. Biochem. Biophys. Res. Commun.95(3), 1098–1104 (1980).
  • Casbarra A , BiroloL, InfusiniGet al. Conformational analysis of HAMLET, the folding variant of human α-lactalbumin associated with apoptosis. Protein Sci. 13(5), 1322–1330 (2004).
  • Svensson M , FastJ, MossbergAKet al. α-lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human α-lactalbumin made lethal to tumor cells). Protein Sci. 12(12), 2794–2804 (2003).
  • Pettersson-Kastberg J , MossbergAK, TrulssonMet al. α-lactalbumin, engineered to be nonnative and inactive, kills tumor cells when in complex with oleic acid: a new biological function resulting from partial unfolding. J. Mol. Biol. 394(5), 994–1010 (2009).
  • Tolin S , De FranceschiG, SpolaoreBet al. The oleic acid complexes of proteolytic fragments of α-lactalbumin display apoptotic activity. FEBS J. 277(1), 163–173 (2010).
  • Svensson M , MossbergAK, PetterssonJ, LinseS, SvanborgC. Lipids as cofactors in protein folding: stereo-specific lipid-protein interactions are required to form HAMLET (human α-lactalbumin made lethal to tumor cells).Protein Sci.12(12), 2805–2814 (2003).
  • Permyakov SE , KnyazevaEL, LeontevaMVet al. A novel method for preparation of HAMLET-like protein complexes. Biochimie 93(9), 1495–1501 (2011).
  • Permyakov SE , KnyazevaEL, KhasanovaLMet al. Oleic acid is a key cytotoxic component of HAMLET-like complexes. Biol Chem. 393(1–2), 85–92 (2012).
  • James Ho CS , PetterStorm, AnnaRydströmet al. Lipids as tumoricidal components of HAMLET; unique and shared effects on signaling and death. In: The Mechanism of HAMLET-Induced Cell Death – Cellular Signalling, Oncogenes and Clinical Perspectives. Lunds Universitet, Sweden (2012).
  • Mossberg AK , PuchadesM, HalskauOet al. HAMLET interacts with lipid membranes and perturbs their structure and integrity. PLoS ONE 5(2), e9384 (2010).
  • Baumann A , GjerdeAU, YingMet al. HAMLET forms annular oligomers when deposited with phospholipid monolayers. J. Mol. Biol. 418(1–2), 90–102 (2012).
  • Storm P , KlausenTJ, TrulssonMet al. A unifying mechanism for tumor cell death by ion channel activation. PLoS One (In Press).
  • Baritaki S , ApostolakisS, KanellouP, Dimanche-BoitrelMT, SpandidosDA, BonavidaB. Reversal of tumor resistance to apoptotic stimuli by alteration of membrane fluidity: therapeutic implications.Adv. Cancer Res.98, 149–190 (2007).
  • Duringer C , HamicheA, GustafssonL, KimuraH, SvanborgC. HAMLET interacts with histones and chromatin in tumor cell nuclei.J. Biol. Chem.278(43), 42131–42135 (2003).
  • Kohler C , HakanssonA, SvanborgC, OrreniusS, ZhivotovskyB. Protease activation in apoptosis induced by MAL.Exp. Cell Res.249(2), 260–268 (1999).
  • Wenzel T , BaumeisterW. Conformational constraints in protein degradation by the 20S proteasome.Nat. Struct. Biol.2(3), 199–204 (1995).
  • Gustafsson L , AitsS, OnnerfjordP, TrulssonM, StormP, SvanborgC. Changes in proteasome structure and function caused by HAMLET in tumor cells.PLoS ONE4(4), e5229 (2009).
  • Brest P , GustafssonM, MossbergAKet al. Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET. Cancer Res. 67(23), 11327–11334 (2007).
  • Hallgren O , GustafssonL, IrjalaH, SelivanovaG, OrreniusS, SvanborgC. HAMLET triggers apoptosis but tumor cell death is independent of caspases, Bcl-2 and p53.Apoptosis11(2), 221–233 (2006).
  • Rammer P , Groth-PedersenL, KirkegaardTet al. BAMLET activates a lysosomal cell death program in cancer cells. Mol. Cancer Ther. 9(1), 24–32 (2010).
  • Aits S , GustafssonL, HallgrenOet al. HAMLET (human α-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death. Int. J. Cancer 124(5), 1008–1019 (2009).
  • Baehrecke EH . Autophagy: dual roles in life and death?Nat. Rev. Mol. Cell Biol.6(6), 505–510 (2005).
  • Debnath J , BaehreckeEH, KroemerG. Does autophagy contribute to cell death?Autophagy1(2), 66–74 (2005).
  • Codogno P , MeijerAJ. Autophagy and signaling: their role in cell survival and cell death.Cell Death Differ.12(Suppl. 2), S1509–S1518 (2005).
  • Trulsson M , YuH, GisselssonLet al. HAMLET binding to α-actinin facilitates tumor cell detachment. PLoS ONE 6(3), e17179 (2011).
  • Menez J , Le Maux ChansacB, DorotheeGet al. Mutant α-actinin-4 promotes tumorigenicity and regulates cell motility of a human lung carcinoma. Oncogene 23(15), 2630–2639 (2004).
  • Gonzalez AM , OteyC, EdlundM, JonesJC. Interactions of a hemidesmosome component and actinin family members.J. Cell Sci.114(Pt 23), 4197–4206 (2001).
  • Franzot G , SjoblomB, GautelM, Djinovic CarugoK. The crystal structure of the actin binding domain from α-actinin in its closed conformation: structural insight into phospholipid regulation of α-actinin.J. Mol. Biol.348(1), 151–165 (2005).
  • Otey CA , VasquezGB, BurridgeK, EricksonBW. Mapping of the α-actinin binding site within the β1 integrin cytoplasmic domain.J. Biol. Chem.268(28), 21193–21197 (1993).
  • Zaidel-Bar R , ItzkovitzS, Ma’ayanA, IyengarR, GeigerB. Functional atlas of the integrin adhesome.Nat. Cell Biol.9(8), 858–867 (2007).
  • Pettersson J , MossbergAK, SvanborgC. α-lactalbumin species variation, HAMLET formation, and tumor cell death. Biochem. Biophys. Res. Commun.345(1), 260–270 (2006).
  • Wilhelm K , DarinskasA, NoppeWet al. Protein oligomerization induced by oleic acid at the solid-liquid interface – equine lysozyme cytotoxic complexes. FEBS J. 276(15), 3975–3989 (2009).
  • Brinkmann CR , HeegaardCW, PetersenTE, JenseniusJC, ThielS. The toxicity of bovine α-lactalbumin made lethal to tumor cells is highly dependent on oleic acid and induces killing in cancer cell lines and noncancer-derived primary cells.FEBS J.278(11), 1955–1967 (2011).
  • Cury-Boaventura MF , PompeiaC, CuriR. Comparative toxicity of oleic acid and linoleic acid on Jurkat cells.Clin. Nutr.23(4), 721–732 (2004).
  • Knyazeva EL , GrishchenkoVM, FadeevRS, AkatovVS, PermyakovSE, PermyakovEA. Who is Mr. HAMLET? Interaction of human α-lactalbumin with monomeric oleic acid.Biochemistry47(49), 13127–13137 (2008).
  • Zhu Y , SchwarzS, AhlemeyerB, GrzeschikS, KlumppS, KrieglsteinJ. Oleic acid causes apoptosis and dephosphorylates Bad.Neurochem. Int.46(2), 127–135 (2005).
  • Yang F Jr , ZhangM, ChenJ, LiangY. Structural changes of α-lactalbumin induced by low pH and oleic acid.Biochim. Biophys. Acta1764(8), 1389–1396 (2006).
  • Liskova K , KellyAL, O’brienN, BrodkorbA. Effect of denaturation of α-lactalbumin on the formation of BAMLET (bovine α-lactalbumin made lethal to tumor cells).J. Agric. Food Chem.58(7), 4421–4427 (2010).
  • Liskova K , AutyMaE, ChaurinVet al. Cytotoxic complexes of sodium oleate with β-lactoglobulin. Eur. J. Lipid. Sci. Tech. 113(10), 1207–1218 (2011).
  • Mossberg AK , HouY, SvenssonM, HolmqvistB, SvanborgC. HAMLET treatment delays bladder cancer development.J. Urol.183(4), 1590–1597 (2010).
  • Rainov NG , KrammCM. Vector delivery methods and targeting strategies for gene therapy of brain tumors.Curr. Gene Ther.1(4), 367–383 (2001).
  • Laske DW , YouleRJ, OldfieldEH. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors.Nat. Med.3(12), 1362–1368 (1997).
  • Mahesparan R , TysnesBB, ReadTA, EngerPO, BjerkvigR, Lund-JohansenM. Extracellular matrix-induced cell migration from glioblastoma biopsy specimens in vitro.Acta Neuropathol. (Berl.)97(3), 231–239 (1999).
  • de Villiers EM . Papillomavirus and HPV typing.Clin. Dermatol.15(2), 199–206 (1997).
  • Bunney MH , NolanMW, WilliamsDA. An assessment of methods of treating viral warts by comparative treatment trials based on a standard design.Br. J. Dermatol.94(6), 667–679 (1976).
  • Mancuso JE , AbramowSP, DimichinoBR, LandsmanMJ. Carbon dioxide laser management of plantar verruca: a 6-year follow-up survey.J. Foot Surg.30(3), 238–243 (1991).
  • Stender IM , NaR, FoghH, GluudC, WulfHC. Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: randomised double-blind trial.Lancet355(9208), 963–966 (2000).
  • Hursthouse MW . A controlled trial on the use of topical 5-fluorouracil on viral warts.Br. J. Dermatol.92(1), 93–96 (1975).
  • Yilmaz E , AlpsoyE, BasaranE. Cimetidine therapy for warts: a placebo-controlled, double-blind study.J. Am. Acad. Dermatol.34(6), 1005–1007 (1996).
  • Leman JA , BentonEC. Verrucas. Guidelines for management.Am. J. Clin. Dermatol.1(3), 143–149 (2000).
  • Gibbs S , HarveyI, SterlingJ, StarkR. Local treatments for cutaneous warts: systematic review.BMJ325(7362), 461 (2002).
  • Harwood CA , SurentheranT, McgregorJMet al. Human papillomavirus infection and nonmelanoma skin cancer in immunosuppressed and immunocompetent individuals. J. Med. Virol. 61(3), 289–297 (2000).
  • Sengupta N , SiddiquiE, MumtazFH. Cancers of the bladder.J. R. Soc. Health124(5), 228–229 (2004).
  • Hudson MA , HerrHW. Carcinoma in situ of the bladder.J. Urol.153(3 Pt 1), 564–572 (1995).
  • Stein JP , LieskovskyG, CoteRet al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J. Clin. Oncol. 19(3), 666–675 (2001).
  • Hakansson A , SvenssonM, MossbergAKet al. A folding variant of α-lactalbumin with bactericidal activity against Streptococcus pneumoniae. Mol. Microbiol. 35(3), 589–600 (2000).
  • Hakansson AP , Roche-HakanssonH, MossbergAK, SvanborgC. Apoptosis-like death in bacteria induced by HAMLET, a human milk lipid-protein complex.PLoS ONE6(3), e17717 (2011).
  • Bosch FX , ManosMM, MunozNet al. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. International biological study on cervical cancer (IBSCC) Study Group. J. Natl Cancer Inst. 87(11), 796–802 (1995).

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