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Targeting the RARα-Gankyrin-PI3K axis with retinoid analogs to modulate autophagy in breast cancer cells:
Pijush Kanti Khanra1, Thirukumaran Kandasamy1, Siddhartha Sankar Ghosh2
1Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, 39, Guwahati, Assam, India.
Abstract:
This study explores the therapeutic potential of Retinoid analogs to overcome this resistance by modulating autophagy and lysosomal activity in breast cancer. Comprehensive bioinformatics analyses such as gene correlation, mutation, co-expression, and functional network analysis revealed a strong correlation between RARα, NRF2, Gankyrin, p110α, and p110β, alongside the PI3K/Akt/mTOR axis in regulating autophagy. Given its upstream role, RARα was identified as the primary target, with NRF2, Gankyrin, p110α, and p110β serving as co-target macromolecules to influence downstream autophagy pathways. Molecular docking analyses identified six RAR agonists-CD437, BMS961, CD437-13C6, Adapalene, Adapalene-d3, and CD1530-as promising candidates, all exhibiting high-profile binding affinities with all 5 target proteins RARα (< -10 kcal/mol), NRF2 (< -7.6 kcal/mol), Gankyrin (< -7.4 kcal/mol), p110α (< -8.9 kcal/mol), and p110β (< -8.6 kcal/mol). Among all, Adapalene (a synthetic Retinoid analog) was selected as a potent multi-target drug based on average docking score. Further, molecular dynamics simulation studies demonstrated enhanced protein stability with notable binding free energies of -82.712 kJ/mol (Gankyrin) and -25.526 kJ/mol (p110α). Subsequent in vitro validation using MCF7 and MDA-MB-468 breast cancer cell lines corroborated the computational findings. Adapalene markedly inhibited autophagy by downregulating the proteomic conversion of the core autophagy marker LC3B-I/LC3B-II, with reductions of up to 2.99-fold in MCF7 and 1.11-fold in MDA-MB-468 cell lines. In addition, it suppressed lysosomal activity by 2.73-fold in MCF7 and 2.52-fold in MDA-MB-468, as demonstrated by lysotracker assays. These findings underscore the potential of Adapalene as a multi-targeted modulator of RARα-PI3K signaling, effectively disrupting autophagy and cancer cell survival mechanisms in luminal and triple-negative breast cancer cells.
Insights
This study identifies Adapalene as a potential breast cancer treatment by targeting key proteins involved in autophagy and lysosomal activity. Adapalene effectively inhibits cancer cell survival by disrupting these crucial cellular processes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer resistance to therapy often involves complex signaling pathways.
- Autophagy and lysosomal activity play critical roles in cancer cell survival and drug resistance.
- Retinoid analogs offer potential therapeutic strategies by modulating these cellular processes.
Purpose of the Study:
- To explore the therapeutic potential of Retinoid analogs in breast cancer by targeting autophagy and lysosomal activity.
- To identify key molecular targets and drug candidates for overcoming therapeutic resistance.
- To investigate the multi-targeted effects of Adapalene on breast cancer cell lines.
Main Methods:
- Comprehensive bioinformatics analyses including gene correlation, mutation, co-expression, and functional network analysis.
- Molecular docking and dynamics simulation studies to identify and evaluate drug candidates.
- In vitro validation using MCF7 and MDA-MB-468 breast cancer cell lines to assess Adapalene's efficacy.
Main Results:
- Identified a strong correlation between RARα, NRF2, Gankyrin, p110α, and p110β in regulating autophagy via the PI3K/Akt/mTOR axis.
- Adapalene demonstrated high binding affinities with target proteins and was selected as a potent multi-target drug.
- Adapalene significantly inhibited autophagy and suppressed lysosomal activity in breast cancer cell lines.
Conclusions:
- Adapalene acts as a multi-targeted modulator of RARα-PI3K signaling, disrupting autophagy and cancer cell survival.
- These findings highlight Adapalene's potential as a therapeutic agent for luminal and triple-negative breast cancer.
- The study provides a strong rationale for further clinical investigation of Adapalene in breast cancer treatment.
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