title: Chorein addiction in VPS13A overexpressing rhabdomyosarcoma cells.
abstract: 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.
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Sabina
authors: S
authors: Honisch
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Willi
authors: W
authors: Yu
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Guilai
authors: G
authors: Liu
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Ioana
authors: I
authors: Alesutan
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Syeda T
authors: ST
authors: Towhid
authors: Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.
authors: Anna
authors: A
authors: Tsapara
authors: Department of Hematology and Oncology, Children's Hospital, University Hospital of Tuebingen, Tübingen, Germany.
authors: Sabine
authors: S
authors: Schleicher
authors: Department of Hematology and Oncology, Children's Hospital, University Hospital of Tuebingen, Tübingen, Germany.
authors: Rupert
authors: R
authors: Handgretinger
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.|Department of Biochemistry, University of Crete Medical School, Heraklion, Greece.
authors: Christos
authors: C
authors: Stournaras
authors: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors: Florian
authors: F
authors: Lang
mesh_terms: D018938:Caco-2 Cells; D002648:Child; D005260:Female; D006801:Humans; D054546:Neuroacanthocytosis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D033921:Vesicular Transport Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; C429654:VPS13A protein, human; D033921:Vesicular Transport Proteins
keywords: BCL-2; Bax; PI-3K; apoptosis; cancer