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Nanoformulated cell-penetrating survivin mutant and its dual actions
Bhasker Sriramoju1, Rupinder K Kanwar1, Jagat R Kanwar1
1Nanomedicine Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine, Faculty of Health, Deakin University, Geelong, Australia.
Abstract:
In this study, we investigated the differential actions of a dominant-negative survivin mutant (SurR9-C84A) against cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons. In both the cases, the mutant protein displayed dual actions, where its effects were cytotoxic toward cancerous cells and proliferative toward the differentiated neurons. This can be explained by the fact that tumorous (undifferentiated SK-N-SH) cells have a high endogenous survivin pool and upon treatment with mutant SuR9-C84A causes forceful survivin expression. These events significantly lowered the microtubule dynamics and stability, eventually leading to apoptosis. In the case of differentiated SK-N-SH neurons that express negligible levels of wild-type survivin, the mutant indistinguishably behaved in a wild-type fashion. It also favored cell-cycle progression, forming the chromosome-passenger complex, and stabilized the microtubule-organizing center. Therefore, mutant SurR9-C84A represents a novel therapeutic with its dual actions (cytotoxic toward tumor cells and protective and proliferative toward neuronal cells), and hence finds potential applications against a variety of neurological disorders. In this study, we also developed a novel poly(lactic-co-glycolic acid) nanoparticulate formulation to surmount the hurdles associated with the delivery of SurR9-C84A, thus enhancing its effective therapeutic outcome.
Insights
A novel survivin mutant (SurR9-C84A) shows dual action: it kills neuroblastoma cancer cells while promoting growth in healthy neurons. This offers potential for treating neurological disorders.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Survivin is a key protein in cell division and survival.
- Cancer cells often overexpress survivin, contributing to tumor growth.
- Targeting survivin offers a potential therapeutic strategy for cancer and neurological diseases.
Purpose of the Study:
- To investigate the differential effects of a dominant-negative survivin mutant (SurR9-C84A) on cancerous neuroblastoma cells and differentiated neurons.
- To explore the therapeutic potential of SurR9-C84A for neurological disorders.
- To develop an effective delivery system for SurR9-C84A.
Main Methods:
- Utilized cancerous SK-N-SH neuroblastoma cell lines and differentiated SK-N-SH neurons.
- Administered the dominant-negative survivin mutant SurR9-C84A.
- Developed a poly(lactic-co-glycolic acid) nanoparticulate formulation for drug delivery.
Main Results:
- SurR9-C84A exhibited cytotoxic effects on cancerous neuroblastoma cells by disrupting microtubule dynamics and inducing apoptosis.
- In differentiated neurons, SurR9-C84A acted similarly to wild-type survivin, promoting cell-cycle progression and microtubule stability.
- A novel PLGA nanoparticle formulation enhanced the delivery and therapeutic efficacy of SurR9-C84A.
Conclusions:
- Mutant SurR9-C84A demonstrates dual therapeutic potential: cytotoxic to tumors and protective/proliferative to neurons.
- SurR9-C84A holds promise for treating neurological disorders.
- The developed nanoparticle formulation improves SurR9-C84A delivery, enhancing its therapeutic outcomes.
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