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Journal article
Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo
Biomedicines, v 11(2), 258
18 Jan 2023
PMID: 36830797
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Any gene therapy for cancer will be predicated upon its selectivity against cancer cells and non-toxicity to normal cells. Therefore, safeguards are needed to prevent its activation in normal cells. We designed a minimal p14(ARF) promoter with upstream Ap1 and E2F enhancer elements and a downstream MDR1 inhibitory element, TATA box, and a transcription initiation site (hereafter p14(ARF)min). The modified p14(ARF)min promoter was linked to bicistronic P14 and truncated BID (tBID) genes, which led to synergistic apoptosis via the intrinsic and extrinsic pathways of apoptosis when expressed. The promoter was designed to be preferentially activated by mutant Ras and completely inhibited by wild-type p53 so that only cells with both mutant Ras and mutant p53 would activate the construct. In comparison to most p53 gene therapies, this construct has selective advantages: (1) p53-based gene therapies with a constitutive CMV promoter cannot differentiate between normal cells and cancer cells, and can be toxic to normal cells; (2) our construct does not induce p21(WAF/CIPI) in contrast to other p53-based gene therapies, which can induce cell cycle arrest leading to increased chemotherapy resistance; (3) the modified construct (p14(ARF)min-p14-tBID) demonstrates bidirectional control of its promoter, which is completely repressed by wild-type p53 and activated only in cells with both RAS and P53 mutations; and (4) a novel combination of genes (p14 and tBID) can synergistically induce potent intrinsic and extrinsic apoptosis in cancer cells.
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Details
- Title
- Gene Therapy with p14/tBID Induces Selective and Synergistic Apoptosis in Mutant Ras and Mutant p53 Cancer Cells In Vitro and In Vivo
- Creators
- Robert L. L. Fine - Columbia University Irving Medical CenterYuehua Mao - Columbia University Irving Medical CenterDario Garcia-Carracedo - Columbia University Irving Medical CenterGloria H. H. Su - Columbia University Irving Medical CenterWanglong Qiu - Columbia Univ, Herbert Irving Comprehens Canc Ctr, Dept Pathol & Otolaryngol, NYPH,Med Ctr, New York, NY 10032 USAUri Hochfeld - Columbia UniversityGwen Nichols - Columbia UniversityYong-Liang Li - Columbia UniversityRichard D. Dinnen - Columbia University Irving Medical CenterAnthony Raffo - Columbia UniversityPaul W. W. Brandt-Rauf - Drexel University, School of Biomedical Engineering, Science, and Health Systems
- Publication Details
- Biomedicines, v 11(2), 258
- Publisher
- MDPI
- Number of pages
- 21
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000944789400001
- Scopus ID
- 2-s2.0-85148899126
- Other Identifier
- 991021860716704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Medicine, Research & Experimental
- Pharmacology & Pharmacy