Multimeric alpha-lactalbumin from human milk induces apoptosis through a direct effect on cell nuclei

A fraction from human milk containing spf-multimer alpha-lactalbumin (MAL) induces apoptosis in tumor cells and immature cells but spares mature cells . The mechanism of apoptosis induction and the molecular basis for the diff erence in susceptibility between tumor cells and healthy cells have not bee n defined. In this study we examined the interaction of MAL with different cellular compartments, using confocal microscopy and subcellular fractionat ion, MAL was shown to accumulate in the nuclei of sensitive cells rather th an in the cytosol, the vesicular fraction, or the ER-Golgi complex. Nuclear uptake occurred rapidly in cells that were susceptible to the apoptosis-in ducing effect, but not in nuclei of resistant cells. Nuclear uptake was thr ough the nuclear pore complex and was critical for the induction of DNA fra gmentation, since inhibition of nuclear uptake with WGA rescued digitonin-p ermeabilized cells from induction of DNA fragmentation. Ca2+ was required f or MAL-induced DNA fragmentation but nuclear uptake of MAL was independent of Ca2+. This way MAL differs from most previously described agents in that it crosses the plasma membrane and cytosol, and enters cell nuclei where i t induces DNA fragmentation through a direct effect at the nuclear level, ( C) 1999 Academic Press.