title: Upregulation of Akt/NF-κB-regulated inflammation and Akt/Bad-related apoptosis signaling pathway involved in hepatic carcinoma process: suppression by carnosic acid nanoparticle.
abstract: Primary liver cancer is globally the sixth most frequent cancer, and the second leading cause of cancer death and its incidence is increasing in many countries, becoming a serious threat to human health. Many researches focused on the treatment and prevention of liver cancer. However, due to the underlying molecular mechanism of liver cancer still not fully understood, the studies and development of treatments were forced to be delayed. Akt has been suggested to play an essential role in the progression of inflammation response and apoptosis. Hence, in this study, Akt-knockout mice and cells of liver cancer were used as a model to investigate the molecular mechanism of Akt-associated inflammatory and apoptotic signaling pathway linked with NF-κB and Bcl-2-associated death promoter (Bad) for the progression of liver cancer. Carnosic acid (CA), as a phenolic diterpene with anticancer, antibacterial, antidiabetic, as well as neuroprotective properties, is produced by many species from Lamiaceae family. Administration of CA nanoparticles was sufficient to lead to considerable inhibition of liver cancer progression. The results indicated that, compared to the normal liver cells, the expression of Akt was significantly higher in liver cancer cell lines. Also, we found that Akt-knockout cancer cell lines modulated inflammation response and apoptosis via inhibiting NF-κB activation and inducing apoptotic reaction. Our results indicated that the downstream signals, including cytokines regulated by NF-κB and caspase-3-activated apoptosis affected by Bad, were re-modulated for knockout of Akt. And CA nanoparticles, acting as Akt-knockout, could inhibit inflammation and accelerate apoptosis in liver cancer by altering NF-κB activation and activating caspase-3 through Bad pathway. These findings demonstrated that the nanoparticulate drug CA performed its effective role owing to its ability to reduce inflammatory action and enhance apoptosis for the overexpression of NF-κB and Bad via Akt signaling pathway, playing a direct role in liver cancer progression. Thus, nanoparticle CA might be an important and potential choice for the clinical treatment in the future.
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Bo
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Fang
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Zhenran
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pathology and Physiopathology, Guilin Medical University, Guilin, Guangxi, People's Republic of China.
authors.forename: Guangying
authors.initials: G
authors.lastname: Qi
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Xingsi
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Shengguang
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Shuiping
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, Guilin Medical University Affiliated Hospital; Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University.
authors.forename: Songqing
authors.initials: S
authors.lastname: He
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D045784:Abietanes; D000975:Antioxidants; D016328:NF-kappa B; D012333:RNA, Messenger; D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt; C018381:salvin
keywords: Akt-knockout; apoptosis; carnosic acid nanoparticle; inflammation; liver cancer