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Published on: January 11, 2019
Survivin-T34A: molecular mechanism and therapeutic potential
Jonathan R Aspe1, Nathan R Wall
1Center for Health Disparities, Research and Molecular Medicine, Division of Biochemistry and Microbiology, Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA.
Abstract:
The inhibitor of apoptosis protein survivin's threonine 34 to alanine (T34A) mutation abolishes a phosphorylation site for p34(cdc2)-cyclin B1, resulting in initiation of the mitochondrial apoptotic pathway in cancer cells; however, it has little known direct effects on normal cells. The possibility that targeting survivin in this way may provide a novel approach for selective cancer gene therapy has yet to be fully evaluated. Although a flurry of work was undertaken in the late 1990s and early 2000s, only minor advances on this mutant have recently taken place. We recently described that cells generated to express a stable form of the mutant protein released this survivin-T34A to the conditioned medium. When this conditioned medium was collected and deposited on naive tumor cells, conditioned medium T34A was as effective as some chemotherapeutics in the induction of tumor cell apoptosis, and when combined with other forms of genotoxic stressors potentiated their killing effects. We hope with this review to revitalize the T34A field, as there is still much that needs to be investigated. In addition to determining the therapeutic dose and the duration of drug therapy required at the disease site, a better understanding of other key factors is also important. These include knowledge of target cell populations, cell-surface receptors, changes that occur in the target tissue at the molecular and cellular level with progression of the disease, and the mechanism and site of therapeutic action.
Insights
The survivin-T34A mutation can selectively induce apoptosis in cancer cells. Conditioned medium containing survivin-T34A shows therapeutic potential, enhancing genotoxic stress effects and warranting further investigation for cancer gene therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Apoptosis
Background:
- The inhibitor of apoptosis protein survivin plays a role in cancer cell survival.
- A specific mutation, threonine 34 to alanine (T34A), disrupts survivin's phosphorylation, potentially triggering cancer cell death.
- Previous research on survivin-T34A has been limited in recent years.
Purpose of the Study:
- To explore the potential of the survivin-T34A mutant as a selective cancer gene therapy approach.
- To investigate the therapeutic efficacy of survivin-T34A released into conditioned medium.
- To identify key factors for the clinical application of survivin-T34A therapy.
Main Methods:
- Generation of cells expressing a stable form of survivin-T34A.
- Collection and application of conditioned medium containing survivin-T34A to naive tumor cells.
- Evaluation of apoptosis induction and potentiation of genotoxic stress effects.
Main Results:
- Cells engineered to express survivin-T34A release the mutant protein into the conditioned medium.
- Conditioned medium containing survivin-T34A effectively induced apoptosis in tumor cells, comparable to some chemotherapeutics.
- Survivin-T34A potentiated the killing effects of other genotoxic stressors when used in combination.
Conclusions:
- Survivin-T34A holds promise for selective cancer gene therapy by inducing apoptosis.
- The released survivin-T34A in conditioned medium demonstrates significant anti-tumor activity.
- Further research is crucial to determine optimal therapeutic doses, target cell populations, and mechanisms of action for survivin-T34A.
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