FAPP2 gene downregulation increases tumor cell sensitivity to Fas-induced apoptosis

Abstract

The gene for phosphatidylinositol-4-phosphate adaptor-2 (FAPP2) encodes a cytoplasmic lipid transferase with a plekstrin homology domain that has been implicated in vesicle maturation and transport from trans-Golgi to the plasma membrane. The introduction of ribozymes targeting the FAPP2 gene in colon carcinoma cells induced their apoptosis in the presence of Fas agonistic antibody. Furthermore, by quantitative PCR we showed that a siRNA specific to FAPP2, but not a randomized siRNA control, reduced FAPP2 gene expression in tumor cells. Transfection of FAPP2 siRNA into human tumor cells then incubated with FasL resulted in reduction of viable cell numbers. Also, FAPP2 siRNA transfected glioma and breast tumor cells showed significant increases in apoptosis upon incubation with soluble FasL, but the apoptosis did not necessarily correlate with increased Fas expression. These data demonstrate a previously unknown role for FAPP2 in conferring resistance to apoptosis and indicate that FAPP2 may be a target for cancer therapy.

Arabidopsis Accelerated Cell Death 11, ACD11, Is a Ceramide-1-Phosphate Transfer Protein and Intermediary Regulator of Phytoceramide Levels

“…Establishment of ACD11 architecture as a C1P-selective GLTP-fold capable of binding/transferring either C1P or phyto-C1P at similar rates provides insights into how this GLTP superfamily member impacts PCD-related processes regulated by key sphingolipid metabolites. While fungal GLTP (HET-C2) and human FAPP2 (C-terminal GLTP-like domain) have both been implicated in PCD-related processes (Fedorova et al, 2005; Paoletti and Clave, 2007; Tritz et al, 2009), no sphingolipid analyses were performed upon in vivo depletion of these glycosylceramide-selective GLTP-folds.…”

The Tumor Suppressive Role of PATZ1 in Thyroid Cancer: A Matter of Epithelial-Mesenchymal Transition

“…It has been recently indicated as a "stemness factor" [11] and shown to play a critical role in reprogramming somatic cells into pluripotent stem cells [12]. PATZ1 expression is regulated by DNA damage [13] and appears deregulated in different human cancers, suggesting a cancer-related role [14][15][16][17], which appears oncogenic or anti-oncogenic depending on the tumor type and likely on the presence/absence of a wild-type p53 protein with which it interacts [10,13]. Consistently, silencing of PATZ1 expression in a p53-null osteosarcoma cell line enhanced its sensitivity to the proapoptotic chemotherapeutic agent 5-fluorouracil (5FU), while Patz1-/-mouse embryonic fibroblasts show a decreased number of apoptotic cells, either spontaneous or induced by 5FU treatment, compared with wild-type controls [10].…”

Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets

“…The data for a role of FAPP2 in cancer is rather limited. An early study described induction of apoptosis in colon cancer carcinoma cells after incubation with ribozymes targeting FAPP2 in the presence of Fas agonistic antibody [40].…”