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Integrative Multi-Omics and Molecular Simulations Identify PRKCD as a Biological Modulator in Colon Adenocarcinoma:
Mohd Adnan1,2, Arif Jamal Siddiqui1,2, Mousa Alreshidi1,2
1Department of Biology, College of Science, University of Ha'il, Ha'il, Saudi Arabia.
Abstract:
Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. Colon adenocarcinoma (COAD), the most common histological subtype, is characterized by a poor prognosis in advanced stages due to significant molecular heterogeneity. Protein kinase C delta (PKCδ), encoded by PRKCD, is a context-dependent regulatory kinase in tumor biology. Its expression, genomic alterations, and binding interactions with phytochemicals from Phoenix dactylifera were studied using a comprehensive in silico approach. PRKCD was found to be downregulated in all TCGA-COAD tumor subgroups when compared to normal tissue. The survival analysis failed to show a statistically significant association between PRKCD expression and overall or disease-free survival; thus, the protein is more likely to be a biological modulator than a prognostic marker. Mutational profiling revealed missense substitutions and copy number variations in COAD. The drug-like properties of 46 phytochemicals from P. dactylifera were evaluated, and only five compounds passed all the filters. Docking against the C2 regulatory domain of PKCδ (PDB ID: 1YRK) revealed (Z)-4-Methoxy-3,3',5,5'-tetrahydroxystilbene (PubChem CID: 13499471) as the highest-scoring ligand at -7.0 kcal/mol. Rottlerin, the validated PKCδ inhibitor, was used as a positive control and had a score of -7.3 kcal/mol at the same binding site. Both complexes were subjected to 100 ns molecular dynamics (MD) simulations under equated conditions. Several parameters, including backbone RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen-bond counts, principal component analysis (PCA), and free-energy landscape (FEL) profiling, all indicated stable conformations for the two complexes. The lead phytocompound showed very similar behaviour to the positive control, thereby reinforcing its potential as a PRKCD modulator. The results indicate that further experimental studies on P. dactylifera-derived stilbenoids in COAD are warranted.
Insights
This study investigated Protein kinase C delta (PKCδ) in colorectal cancer (CRC), finding it downregulated and a potential biological modulator. A Phoenix dactylifera compound showed promise as a PRKCD modulator.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Colorectal cancer (CRC) presents a significant global health challenge, with colon adenocarcinoma (COAD) being the most common and aggressive subtype.
- Significant molecular heterogeneity in advanced COAD contributes to poor prognosis.
- Protein kinase C delta (PKCδ), encoded by PRKCD, is a kinase with context-dependent roles in tumor biology.
Purpose of the Study:
- To investigate the expression, genomic alterations, and potential therapeutic interactions of PRKCD in COAD.
- To explore the binding affinity of phytochemicals from Phoenix dactylifera with PKCδ.
- To evaluate the stability and potential of a lead phytocompound as a PRKCD modulator.
Main Methods:
- Comprehensive in silico analysis including expression profiling (TCGA-COAD), mutational profiling, and phytochemical screening.
- Molecular docking of P. dactylifera compounds against the PKCδ C2 regulatory domain.
- 100 ns molecular dynamics (MD) simulations to assess complex stability.
Main Results:
- PRKCD was consistently downregulated across TCGA-COAD tumor subgroups compared to normal tissue.
- Survival analysis did not reveal a significant prognostic role for PRKCD expression.
- (Z)-4-Methoxy-3,3',5,5'-tetrahydroxystilbene from P. dactylifera demonstrated high binding affinity to PKCδ, comparable to the known inhibitor Rottlerin.
- MD simulations confirmed stable conformations for both the lead phytocompound-PKCδ and Rottlerin-PKCδ complexes.
Conclusions:
- PKCδ appears to function as a biological modulator rather than a prognostic marker in COAD.
- A P. dactylifera-derived stilbenoid shows significant potential as a PRKCD modulator.
- Further experimental validation of P. dactylifera stilbenoids in COAD is warranted.
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