Epidermal growth factor receptor-dependent stimulation of differentiation by human papillomavirus type 16 E5.

Human papillomaviruses (HPVs) infect keratinocytes of stratified squamous epithelia, and persistent infection with high-risk HPV types, such as HPV16, may lead to the development of malignancies. HPV evades host immunity in part by linking its gene expression to the host differentiation program, and therefore relies on differentiation to complete its life cycle. Based on previous reports indicating that the HPV16 protein E5 is important in the late stages of the differentiation-dependent life cycle, we found that organotypic cultures harboring HPV16 genomes lacking E5 showed reduced markers of terminal differentiation compared to wild type HPV16-containing cultures. We found that epidermal growth factor receptor (EGFR) levels and activation were increased in an E5-depdendent manner in these tissues, and that EGFR promoted terminal differentiation and expression of the HPV16 L1 gene. These findings suggest a function for E5 in preserving the ability of HPV16 containing keratinocytes to differentiate, thus facilitating the production of new virus progeny.

Kaempferol as a Potential PAK4 Inhibitor in Triple Negative Breast Cancer: Extra Precision Glide Docking and Free Energy Calculation.

BACKGROUND: P-21 activating kinase 4 (PAK4) is implicated in poor prognosis of many human tumors, particularly in Triple Negative Breast Cancer (TNBC) progression. Studies have revealed the crucial role of PAK4 in cell proliferation, anchorage-independent growth and cell migration among other hallmarks of cancer. Thus, PAK4 is an attractive target for anti-TNBC drug design and development. In our research, we used in silico methods to investigate the inhibitory potentials of kaempferol against PAK4 as compared with co-crystallized 4T6 and a standard PAK4 inhibitor-KPT-9274. The ligands were docked into the ATP-binding site of the target enzyme and post-docking validations were calculated. RESULTS: In the molecular docking results, kaempferol had higher affinity than the standard KPT-9274. However, the SP and XP docking scores for the co-crystallized 4T6 were the highest. The analyses of the docking showed a favorable interaction between kaempferol and the catalytic-important aminoacyl residues, especially GLU396, LEU398 and ASP458 in the ATP-binding site of PAK4 when compared with what was obtained in the 4T6-PAK4 complex. Molecular mechanics based MM-GBSA was used to validate docking results. The free energy calculations revealed that kaempferol may have a favorable biological activity. Furthermore, the druggability of each ligand was assessed using the QikProp module and the SwissADME online tool. Kaempferol possessed a propitious drug-like property when compared to the standard ligands. CONCLUSIONS: We, therefore, put forward a logical argument that kaempferol can be further evaluated as a potential PAK4 inhibitor in TNBC.