Restoring FAS Expression via Lipid-Encapsulated FAS DNA Nanoparticle Delivery Is Sufficient to Suppress Colon Tumor Growth In Vivo.

Autor: Merting AD; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA., Poschel DB; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA., Lu C; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA., Klement JD; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA., Yang D; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA., Li H; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA., Shi H; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA., Chapdelaine E; Genprex Inc., Austin, TX 78746, USA., Montgomery M; Genprex Inc., Austin, TX 78746, USA., Redman MT; Genprex Inc., Austin, TX 78746, USA., Savage NM; Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA., Nayak-Kapoor A; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA., Liu K; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.; Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA.; Charlie Norwood VA Medical Center, Augusta, GA 30904, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Jan 12; Vol. 14 (2). Date of Electronic Publication: 2022 Jan 12.
DOI: 10.3390/cancers14020361
Abstrakt: A hallmark of human colorectal cancer is lost expression of FAS, the death receptor for FASL of cytotoxic T lymphocytes (CTLs). However, it is unknown whether restoring FAS expression alone is sufficient to suppress csolorectal-cancer development. The FAS promoter is hypermethylated and inversely correlated with FAS mRNA level in human colorectal carcinomas. Analysis of single-cell RNA-Seq datasets revealed that FAS is highly expressed in epithelial cells and immune cells but down-regulated in colon-tumor cells in human colorectal-cancer patients. Codon usage-optimized mouse and human FAS cDNA was designed, synthesized, and encapsulated into cationic lipid to formulate nanoparticle DOTAP-Chol-mFAS and DOTAP-Chol-hFAS, respectively. Overexpression of codon usage-optimized FAS in metastatic mouse colon-tumor cells enabled FASL-induced elimination of FAS + tumor cells in vitro, suppressed colon tumor growth, and increased the survival of tumor-bearing mice in vivo. Overexpression of codon-optimized FAS-induced FAS receptor auto-oligomerization and tumor cell auto-apoptosis in metastatic human colon-tumor cells. DOTAP-Chol-hFAS therapy is also sufficient to suppress metastatic human colon tumor xenograft growth in athymic mice. DOTAP-Chol-mFAS therapy exhibited no significant liver toxicity. Our data determined that tumor-selective delivery of FAS DNA nanoparticles is sufficient for suppression of human colon tumor growth in vivo.
Databáze: MEDLINE
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