Mitochondrially Targeted p53-Bad* Fusion Gene Therapy Promotes Apoptosis in Hepatocellular Carcinoma by Pan-Bcl-2
Braxten D Hornsby1, Julius K K Tuekpe1, Cassidy A Steele1
1Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah 84112, United States.
Abstract:
Presenting a considerable disease burden and global health threat, hepatocellular carcinoma (HCC) is in desperate need of potent and effective therapies. p53-Bad* is designed to provide mitochondrial targeting, enhance binding interactions with antiapoptotic Bcl-2 family members, and improve apoptotic activity in various cancers. While we have shown that fusion of p53 and Bad* improves mitochondrial localization and increases apoptosis in HCC, critically, the mechanism of action and nature of this heightened apoptotic function have not been delineated. Here, the functional activity and apoptotic mechanism of action of our p53-Bad* construct was explored, demonstrating that fusion of pro-apoptotic Bad* to p53 does indeed enhance interactions with antiapoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL relative to p53-WT. We confirm that p53-Bad* acts as a pro-apoptotic agent specifically at the mitochondria by inhibition and blockade of downstream Bak/Bax oligomerization events, rescuing cells from p53-Bad*-induced cytotoxicity and apoptosis. Using mutant p53-Bad* variants designed to disrupt binding interactions with antiapoptotic targets, a direct relationship between functional binding interactions and the apoptotic activity of p53-Bad* is established. These findings present strong evidence for the use of p53-Bad* as a pan-Bcl-2 inhibitor and synergistic pro-apoptotic agent in cancers with upregulation of multiple antiapoptotic and prognostic markers.
Insights
The novel p53-Bad* fusion protein enhances apoptosis in hepatocellular carcinoma by targeting mitochondria and inhibiting antiapoptotic proteins. This promotes cancer cell death, offering a potential new therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) poses a significant global health challenge, necessitating novel therapeutic strategies.
- The p53-Bad* fusion protein is engineered for mitochondrial targeting to enhance apoptosis in cancer cells.
- Previous studies indicated improved mitochondrial localization and apoptosis in HCC with p53-Bad*, but the precise mechanism remained unclear.
Purpose of the Study:
- To elucidate the functional activity and apoptotic mechanism of the p53-Bad* construct in hepatocellular carcinoma.
- To investigate the interactions of p53-Bad* with antiapoptotic Bcl-2 family members.
- To establish the relationship between binding interactions and apoptotic efficacy.
Main Methods:
- Comparative analysis of p53-Bad* and wild-type p53 (p53-WT) interactions with Bcl-2 family members (Mcl-1, Bcl-2, Bcl-xL).
- Assessment of p53-Bad*'s effect on mitochondrial Bak/Bax oligomerization.
- Utilizing mutant p53-Bad* variants to probe binding-dependent apoptotic activity.
Main Results:
- p53-Bad* demonstrated enhanced binding to Mcl-1, Bcl-2, and Bcl-xL compared to p53-WT.
- The construct functions as a mitochondrial pro-apoptotic agent by inhibiting Bak/Bax oligomerization.
- Mutant variants confirmed a direct correlation between functional binding and apoptotic activity, mitigating cytotoxicity.
Conclusions:
- Fusion of pro-apoptotic Bad* to p53 effectively enhances interactions with multiple antiapoptotic Bcl-2 proteins.
- p53-Bad* acts as a mitochondrial pro-apoptotic agent by blocking Bak/Bax oligomerization, leading to cancer cell death.
- These findings support p53-Bad* as a pan-Bcl-2 inhibitor and synergistic agent for cancers with upregulated antiapoptotic markers.
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