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Preclinical Targeting of the PGRMC1-CK2 Axis with Silmitasertib: A Potential Strategy for Lung Adenocarcinoma Therapy
S Solaipriya1, M Anbalagan2, V Sivaramakrishnan1
1Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur Campus, Chennai - 603203, Tamil Nadu, India.
Abstract:
Progesterone receptor membrane component 1 (PGRMC1) is a pleiotropic protein over-expressed in lung adenocarcinoma (LUAD). The precise molecular mechanisms underlying the signature motif of Casein kinase (CK2) presence in PGRMC1 and their role in LUAD remain unclear. X-ray crystallographic structure for CK2 and PGRMC1 from the PubChem database was obtained and subjected to protein-protein interaction (PPI) analysis to identify their interactions. In addition, the CK2 inhibitor - Silmitasertib was also utilised to understand the interaction between PGRMC1-CK2. The PPI complex (PGRMC1-CK2) and the PPI-ligand interaction analysis and their Molecular Dynamics (MD) studies revealed the stability of their interactions and critical amino acid contacts within the 5Ǻ vicinity of the CK2 signature motif "T/S-x-x-E/D". Moreover, in-vitro colony formation assay, migration assay, and gene expression analysis using quantitative Real-time PCR revealed that Silmitasertib (IC50-2.5 μM) was highly influential in suppressing the PGRMC1-CK2 expression axis. In conclusion, our study infers that PGRMC1-CK-2 axis inhibition could be a potential therapeutic option to limit the promotion and progression of lung cancer.
Insights
Targeting the Progesterone receptor membrane component 1 (PGRMC1)-Casein kinase (CK2) axis with Silmitasertib shows promise for inhibiting lung adenocarcinoma (LUAD) progression by suppressing key interactions and gene expression.
Area of Science:
- Molecular Biology
- Biochemistry
- Oncology
Background:
- Progesterone receptor membrane component 1 (PGRMC1) is over-expressed in lung adenocarcinoma (LUAD).
- The specific role of Casein kinase (CK2) interaction with PGRMC1 in LUAD is not fully understood.
- Understanding this interaction is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the molecular mechanisms of PGRMC1-CK2 interaction in LUAD.
- To investigate the therapeutic potential of inhibiting the PGRMC1-CK2 axis.
- To evaluate the efficacy of the CK2 inhibitor Silmitasertib.
Main Methods:
- Obtained X-ray crystallographic structures of CK2 and PGRMC1.
- Performed protein-protein interaction (PPI) and Molecular Dynamics (MD) analyses.
- Utilized Silmitasertib to study PGRMC1-CK2 inhibition, alongside in-vitro assays (colony formation, migration, qRT-PCR).
Main Results:
- Identified stable interactions between PGRMC1 and CK2, with critical amino acid contacts near the CK2 motif.
- Silmitasertib demonstrated significant suppression of the PGRMC1-CK2 expression axis (IC50 = 2.5 μM).
- In-vitro assays confirmed Silmitasertib's inhibitory effects on LUAD cell proliferation and migration.
Conclusions:
- The PGRMC1-CK2 axis plays a significant role in LUAD progression.
- Inhibition of the PGRMC1-CK2 axis using Silmitasertib is a potential therapeutic strategy for lung cancer.
- Further research into this axis could lead to novel lung cancer treatments.
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