BAMLET activates a lysosomal cell death program in cancer cells.
Paul Rammer,Line Groth-Pedersen,Thomas Kirkegaard,Mads Daugaard,Anna Rytter,Piotr Szyniarowski,Maria Høyer-Hansen,Lou Klitgaard Povlsen,Jesper Nylandsted,Jakob E. Larsen,Marja Jäättelä +10 more
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TLDR
Data indicate that BAMLET triggers lysosomal cell death pathway in cancer cells, thereby clarifying the ability of α-lactalbumin:oleate complexes to kill highly apoptosis-resistant tumor cells.Abstract:
A complex of human alpha-lactalbumin and oleic acid (HAMLET) was originally isolated from human milk as a potent anticancer agent. It kills a wide range of transformed cells of various origins while leaving nontransformed healthy cells largely unaffected both in vitro and in vivo. Importantly, purified alpha-lactalbumins from other mammals form complexes with oleic acid that show biological activities similar to that of HAMLET. The mechanism by which these protein-lipid complexes kill tumor cells is, however, largely unknown. Here, we show that complex of bovine alpha-lactalbumin and oleic acid (BAMLET), the bovine counterpart of HAMLET, kills tumor cells via a mechanism involving lysosomal membrane permeabilization. BAMLET shows potent cytotoxic activity against eight cancer cell lines tested, whereas nontransformed NIH-3T3 murine embryonic fibroblasts are relatively resistant. BAMLET accumulates rapidly and specifically in the endolysosomal compartment of tumor cells and induces an early leakage of lysosomal cathepsins into the cytosol followed by the activation of the proapoptotic protein Bax. Ectopic expression of three proteins known to stabilize the lysosomal compartment, i.e. heat shock protein 70 (Hsp70), Hsp70-2, and lens epithelium-derived growth factor, confer significant protection against BAMLET-induced cell death, whereas the antiapoptotic protein Bcl-2, caspase inhibition, and autophagy inhibition fail to do so. These data indicate that BAMLET triggers lysosomal cell death pathway in cancer cells, thereby clarifying the ability of alpha-lactalbumin:oleate complexes to kill highly apoptosis-resistant tumor cells.read more
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Lysosomal cell death at a glance
Sonja Aits,Marja Jäättelä +1 more
TL;DR: Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules, which leads to lysosomal membrane permeabilization.
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Lysosomes and lysosomal cathepsins in cell death.
TL;DR: Impairing autophagy by disabling the lysosome function is being investigated as an adjuvant therapeutic approach to sensitize cells to apoptosis-inducing agents as well as a promising strategy in this context as it would not only disable Autophagy, but also promote apoptosis through the initiation of thelysosomal pathway.
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Milk-derived exosomes for oral delivery of paclitaxel
Ashish Kumar Agrawal,Farrukh Aqil,Jeyaprakash Jeyabalan,Wendy A. Spencer,Joshua Beck,Beth W. Gachuki,Sara S. Alhakeem,Karine Z. Oben,Radha Munagala,Subbarao Bondada,Ramesh C. Gupta +10 more
TL;DR: In this article, milk-derived exosomes have been investigated for oral delivery of the chemotherapeutic drug paclitaxel (PAC) as an alternative to conventional i.p. therapy for improved efficacy and reduced toxicity.
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Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay
Sonja Aits,Jennifer Kricker,Bin Liu,Anne-Marie Ellegaard,Saara Hämälistö,Siri Amanda Tvingsholm,Elisabeth Corcelle-Termeau,Søren Høgh,Thomas Farkas,Anna Sofie Holm Jonassen,Irina Gromova,Monika Mortensen,Marja Jäättelä +12 more
TL;DR: The detection of galectin puncta at leaky lysosomes as a highly sensitive and easily manageable assay for LMP opens up new possibilities to study LMP in cell death and its role in other cellular processes such as autophagy, senescence, aging, and inflammation.
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Milk intelligence: Mining milk for bioactive substances associated with human health
Susan Mills,R.P. Ross,R.P. Ross,Colin Hill,Gerald F. Fitzgerald,Catherine Stanton,Catherine Stanton +6 more
TL;DR: Milk has evolved as a complete food for the mammalian nourishment of its young, but research is unveiling an ever-accumulating range of bioactivities associated with milk substituents, emphasizing a role in programming human health.
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