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Published on: November 18, 2022
Searching for combination therapy by clustering methods: Stimulation of PKC in Golgi apparatus combined with
Lenka Lenkavska1, Silvia Tomkova1, Denis Horvath2
1Department of Biophysics, Faculty of Science, P. J. Safarik University in Kosice, 041 54, Kosice, Slovakia.
Abstract:
Cancer cell metabolism is a very attractive target for anticancer treatments. This work focuses on protein kinase C (PKC) signaling in the U87 MG glioma. By means of western blot, fluorescence and time-resolved fluorescence microscopy the correlation between the Golgi apparatus (GA), lysosomes and mitochondria were evaluated. The known regulators of PKC were applied to cancer cells. Phorbol myristate acetate (PMA) was chosen as the activator of PKC. Gö6976, hypericin and rottlerin, the inhibitors of PKCα and PKCδ were selected as well. Stabilization, destabilization processes occurring in cells allow classification of observations into several groups. Multiple versions of hierarchical cluster analysis have been applied and similarities have been found between organelles and PKC regulators. The method identified GA as an extraordinary organelle whose functionality is significantly influenced by PKC regulators as well as oxidative stress. Therefore, combination therapy has been designed according to the results of the cluster analysis. Furthermore, the efficacy of photodynamic therapy mediated by hypericin, and the consequent apoptosis, was significantly increased during the treatment. To our knowledge, this is the first demonstration of the effectiveness of the clustering in the given area.
Insights
This study reveals how protein kinase C (PKC) regulators impact cancer cell organelles, particularly the Golgi apparatus. This finding led to a combination therapy that enhances photodynamic therapy efficacy and cancer cell apoptosis.
Area of Science:
- Cellular Biology
- Cancer Research
- Biochemistry
Background:
- Cancer cell metabolism is a key target for anticancer therapies.
- Protein kinase C (PKC) signaling plays a role in cancer progression.
- Understanding organelle interactions with PKC is crucial for developing new treatments.
Purpose of the Study:
- To investigate the correlation between the Golgi apparatus (GA), lysosomes, and mitochondria in U87 MG glioma cells.
- To evaluate the impact of PKC regulators on these organelles.
- To design a combination therapy based on identified cellular interactions.
Main Methods:
- Western blot, fluorescence, and time-resolved fluorescence microscopy were used to assess organelle correlations.
- PKC activators (PMA) and inhibitors (Gö6976, hypericin, rottlerin) were applied to cancer cells.
- Hierarchical cluster analysis was employed to identify similarities between organelles and PKC regulators.
Main Results:
- The Golgi apparatus (GA) was identified as a critical organelle significantly influenced by PKC regulators and oxidative stress.
- Cluster analysis revealed specific correlations between organelles and PKC pathway modulators.
- A combination therapy strategy was developed based on these findings.
Conclusions:
- PKC signaling profoundly affects the Golgi apparatus and cellular homeostasis in glioma cells.
- The developed combination therapy, incorporating hypericin-mediated photodynamic therapy, significantly enhanced apoptosis.
- This study demonstrates the novel application of cluster analysis for identifying therapeutic targets in cancer research.
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