TY - JOUR
T1 - Liprotides kill cancer cells by disrupting the plasma membrane
AU - Frislev, Henriette S
AU - Boye, Theresa Louise
AU - Nylandsted, Jesper
AU - Otzen, Daniel
PY - 2017/12/1
Y1 - 2017/12/1
N2 - HAMLET (human α-lactalbumin made lethal to tumour cells) is a complex of α-lactalbumin (aLA) and oleic acid (OA) which kills transformed cells, while leaving fully differentiated cells largely unaffected. Other protein-lipid complexes show similar anti-cancer potential. We call such complexes liprotides. The cellular impact of liprotides, while intensely investigated, remains unresolved. To address this, we report on the cell-killing mechanisms of liprotides prepared by incubating aLA with OA for 1 h at 20 or 80 °C (lip20 and lip80, respectively). The liprotides showed similar cytotoxicity against MCF7 cells, though lip80 acts more slowly, possibly due to intermolecular disulphide bonds formed during preparation. Liprotides are known to increase the fluidity of a membrane and transfer OA to vesicles, prompting us to focus on the effect of liprotides on the cell membrane. Extracellular Ca(2+) influx is important for activation of the plasma membrane repair system, and we found that removal of Ca(2+) from the medium enhanced the liprotides' killing effect. Liprotide cytotoxicity was also increased by knockdown of Annexin A6 (ANXA6), a protein involved in plasma membrane repair. We conclude that MCF7 cells counteract liprotide-induced membrane permeabilization by activating their plasma membrane repair system, which is triggered by extracellular Ca(2+) and involves ANXA6.
AB - HAMLET (human α-lactalbumin made lethal to tumour cells) is a complex of α-lactalbumin (aLA) and oleic acid (OA) which kills transformed cells, while leaving fully differentiated cells largely unaffected. Other protein-lipid complexes show similar anti-cancer potential. We call such complexes liprotides. The cellular impact of liprotides, while intensely investigated, remains unresolved. To address this, we report on the cell-killing mechanisms of liprotides prepared by incubating aLA with OA for 1 h at 20 or 80 °C (lip20 and lip80, respectively). The liprotides showed similar cytotoxicity against MCF7 cells, though lip80 acts more slowly, possibly due to intermolecular disulphide bonds formed during preparation. Liprotides are known to increase the fluidity of a membrane and transfer OA to vesicles, prompting us to focus on the effect of liprotides on the cell membrane. Extracellular Ca(2+) influx is important for activation of the plasma membrane repair system, and we found that removal of Ca(2+) from the medium enhanced the liprotides' killing effect. Liprotide cytotoxicity was also increased by knockdown of Annexin A6 (ANXA6), a protein involved in plasma membrane repair. We conclude that MCF7 cells counteract liprotide-induced membrane permeabilization by activating their plasma membrane repair system, which is triggered by extracellular Ca(2+) and involves ANXA6.
KW - Journal Article
UR - http://www.scopus.com/inward/record.url?scp=85033666038&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-15003-6
DO - 10.1038/s41598-017-15003-6
M3 - Journal article
C2 - 29123177
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 15129
ER -