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Published on: February 9, 2019
Spatial targeting of Bcl-2 on endoplasmic reticulum and mitochondria in cancer cells by lipid nanoparticles
Shalini Pandey1, Sohan Patil, Nirmalya Ballav
1Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune, Dr Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India.
Abstract:
The presence of the same proteins at different sub-cellular locations with completely different functions adds to the complexity of signalling pathways in cancer. Subsequently, it becomes indispensable to understand the diverse critical roles of these proteins based on their spatial distribution for the development of improved cancer therapeutics. To address this, in this work, we report the development of endoplasmic reticulum (ER) and mitochondria targeted nanoscale particles to spatially impair anti-apoptotic Bcl-2 protein in these organelles in HeLa cervical cancer cells. Confocal microscopy and gel electrophoresis confirmed that these nanoparticles selectively home into ER and mitochondria and inhibited Bcl-2 localized there. Interestingly, Bcl-2 inhibition in ER induced ER stress leading to autophagy, whereas inhibition of Bcl-2 in mitochondria leads to mitochondrial damage and programmed cell death (apoptosis) in HeLa cells. These nanoscale platforms can be further explored as chemical biology tools to decipher the location-function relationship of proteins towards next generation cancer therapeutics.
Insights
Researchers developed targeted nanoparticles to inhibit the anti-apoptotic Bcl-2 protein in specific cellular locations. This approach revealed distinct cancer cell responses, paving the way for novel cancer therapeutics.
Area of Science:
- Cell Biology
- Cancer Research
- Nanotechnology
Background:
- Proteins can exhibit diverse functions based on their sub-cellular localization, complicating cancer signaling pathways.
- Understanding protein spatial distribution is crucial for developing effective cancer therapeutics.
Purpose of the Study:
- To develop targeted nanoscale particles for spatial inhibition of the anti-apoptotic Bcl-2 protein.
- To investigate the functional consequences of inhibiting Bcl-2 in the endoplasmic reticulum (ER) and mitochondria.
Main Methods:
- Development of endoplasmic reticulum (ER) and mitochondria-targeted nanoscale particles.
- Utilizing confocal microscopy and gel electrophoresis to confirm nanoparticle localization and target inhibition.
- Employing HeLa cervical cancer cells to study cellular responses.
Main Results:
- Nanoparticles selectively targeted and inhibited Bcl-2 in the ER and mitochondria of HeLa cells.
- ER-localized Bcl-2 inhibition induced ER stress and autophagy.
- Mitochondria-localized Bcl-2 inhibition triggered mitochondrial damage and apoptosis.
Conclusions:
- Targeted inhibition of Bcl-2 at specific organelles elicits distinct cellular responses.
- Nanoscale platforms offer potential as chemical biology tools to explore protein location-function relationships.
- This approach could inform the development of next-generation cancer therapeutics.
