Chorein encoded by VPS13A (vacuolar protein sorting-associated
protein 13A) is defective in
chorea-acanthocytosis. Chorein fosters neuronal cell survival, cortical actin polymerization and cell stiffness. In view of its anti-apoptotic effect in neurons, we explored whether chorein is expressed in
cancer cells and influences
cancer cell survival. RT-PCR was employed to determine transcript levels, specific
siRNA to silence chorein, FACS analysis to follow apoptosis and Western blotting to quantify
protein abundance. Chorein transcripts were detected in various
cancer cell types. The
mRNA coding for chorein and chorein
protein were most abundant in
drug resistant, poorly differentiated human
rhabdomyosarcoma cells. Chorein silencing significantly reduced the ratio of phosphorylated (and thus activated) to total
phosphoinositide 3 kinase (PI-3K), pointing to inactivation of this crucial pro-survival signaling molecule. Moreover, chorein silencing diminished transcript levels and
protein expression of anti-apoptotic BCL-2 and enhanced transcript levels of pro-apoptotic Bax. Silencing of chorein in
rhabdomyosarcoma cells was followed by mitochondrial depolarization,
caspase 3 activation and stimulation of early and late apoptosis. In conclusion, chorein is expressed in various
cancer cells. In cells with high chorein expression levels chorein silencing promotes apoptotic cell death, an effect paralleled by down-regulation of
PI-3K activity and BCL-2/Bax expression ratio.