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Published on: February 9, 2024
FAPP2 gene downregulation increases tumor cell sensitivity to Fas-induced apoptosis
Richard Tritz1, Michelle J Hickey, Amy H Lin
1Brain Tumor Research Program, Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
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.
Insights
Phosphatidylinositol-4-phosphate adaptor-2 (FAPP2) promotes cancer cell survival. Inhibiting FAPP2 gene expression can induce apoptosis in tumor cells, suggesting FAPP2 as a potential cancer therapy target.
Area of Science:
- Molecular and Cellular Biology
- Cancer Research
- Cell Signaling
Background:
- Phosphatidylinositol-4-phosphate adaptor-2 (FAPP2) is a cytoplasmic lipid transferase involved in vesicle transport.
- FAPP2's role in cancer cell survival and apoptosis resistance was previously uncharacterized.
Purpose of the Study:
- To investigate the role of FAPP2 in tumor cell apoptosis.
- To evaluate FAPP2 as a potential therapeutic target for cancer treatment.
Main Methods:
- Quantitative PCR (qPCR) to measure FAPP2 gene expression.
- Small interfering RNA (siRNA) to specifically target and reduce FAPP2 expression in various human tumor cells (colon carcinoma, glioma, breast cancer).
- Treatment with Fas agonistic antibody or soluble Fas Ligand (FasL) to induce apoptosis.
- Assessment of cell viability and apoptosis rates.
Main Results:
- siRNA-mediated knockdown of FAPP2 significantly reduced FAPP2 gene expression in tumor cells.
- FAPP2 siRNA transfection led to increased apoptosis in colon carcinoma cells treated with Fas antibody.
- FAPP2 siRNA transfection significantly increased apoptosis in glioma and breast tumor cells upon FasL stimulation, independent of Fas expression levels.
Conclusions:
- FAPP2 plays a critical role in conferring resistance to apoptosis in cancer cells.
- Targeting FAPP2, for instance, through siRNA, represents a promising strategy for cancer therapy.
- FAPP2 is identified as a novel therapeutic target for enhancing cancer cell apoptosis.
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