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Fenretinide Perturbs Focal Adhesion Kinase in Premalignant and Malignant Human Oral Keratinocytes. Fenretinide's
Byungdo B Han1, Suyang Li2, Meng Tong2
1Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio.
Abstract:
The membrane-associated protein, focal adhesion kinase (FAK), modulates cell-extracellular matrix interactions and also conveys prosurvival and proliferative signals. Notably, increased intraepithelial FAK levels accompany transformation of premalignant oral intraepithelial neoplasia (OIN) to oral squamous cell carcinoma (OSCC). OIN chemoprevention is a patient-centric, optimal strategy to prevent OSCC's comorbidities and mortality. The cancer chemopreventive and synthetic vitamin A derivative, fenretinide, has demonstrated protein-binding capacities, for example, mTOR- and retinol-binding protein interactions. These studies used a continuum of human oral keratinocytes (normal-HPV E6/E7-transduced-OSCC) to assess potential fenretinide-FAK drug protein interactions and functional consequences on cellular growth regulation and motility. Molecular modeling studies demonstrated that fenretinide has approximately 200-fold greater binding affinity relative to the natural ligand (ATP) at FAK's kinase domain. Fenretinide also shows intermediate binding at FAK's FERM domain and interacts at the ATP-binding site of the closest FAK analogue, PYK2. Fenretinide significantly suppressed proliferation via induction of apoptosis and G2-M cell-cycle blockade. Fenretinide-treated cells also demonstrated F-actin disruption, significant inhibition of both directed migration and invasion of a synthetic basement membrane, and decreased phosphorylation of growth-promoting kinases. A commercially available FAK inhibitor did not suppress cell invasion. Notably, although FAK's FERM domain directs cell invasion, FAK inhibitors target the kinase domain. In addition, FAK-specific siRNA-treated cells showed an intermediate cell migration capacity; data which suggest cocontribution of the established migrating-enhancing PYK2. Our data imply that fenretinide is uniquely capable of disrupting FAK's and PYK2's prosurvival and mobility-enhancing effects and further extend fenretinide's chemopreventive contributions beyond induction of apoptosis and differentiation.
Insights
Fenretinide disrupts focal adhesion kinase (FAK) and PYK2 signaling, inhibiting oral cancer cell growth, migration, and invasion. This vitamin A derivative offers a novel chemopreventive strategy against oral squamous cell carcinoma (OSCC).
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Focal adhesion kinase (FAK) is crucial for cell-matrix interactions and promotes survival and proliferation.
- Elevated FAK levels correlate with oral intraepithelial neoplasia (OIN) progression to oral squamous cell carcinoma (OSCC).
- Fenretinide, a vitamin A derivative, is a potential chemopreventive agent with known protein-binding capabilities.
Purpose of the Study:
- To investigate fenretinide's interaction with FAK and PYK2 in oral keratinocytes.
- To evaluate the functional consequences of fenretinide-FAK interactions on cancer cell growth, motility, and invasion.
- To explore fenretinide's potential as a chemopreventive agent for OSCC.
Main Methods:
- Molecular modeling to assess fenretinide binding affinity to FAK and PYK2.
- Cell-based assays using normal, HPV-transduced, and OSCC oral keratinocytes.
- Analysis of cell proliferation, apoptosis, cell-cycle progression, F-actin organization, migration, and invasion.
- Comparison with a commercial FAK inhibitor and FAK-specific siRNA.
Main Results:
- Fenretinide exhibits high binding affinity to FAK's kinase domain and intermediate binding to its FERM domain, also interacting with PYK2.
- Fenretinide suppressed oral cancer cell proliferation by inducing apoptosis and G2-M cell-cycle arrest.
- Fenretinide inhibited cell migration and invasion, disrupted F-actin, and reduced phosphorylation of growth-promoting kinases, effects not fully replicated by a FAK inhibitor alone.
Conclusions:
- Fenretinide uniquely disrupts both FAK and PYK2 signaling pathways, inhibiting prosurvival and motility-enhancing effects crucial for OSCC progression.
- Fenretinide demonstrates significant chemopreventive potential against OSCC by targeting multiple oncogenic mechanisms beyond apoptosis and differentiation.
- These findings support fenretinide as a promising therapeutic candidate for OIN chemoprevention, potentially reducing OSCC development and associated mortality.
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