0000000000002696
AUTHOR
John R. Basile
The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma
Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to suc…
Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells.
Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and …
Sex steroid hormone receptors, their ligands, and nuclear and non-nuclear pathways
The ability of a cell to respond to a particular hormone depends on the presence of specific receptors for those hormones. Once the hormone has bound to its receptor, and following structural and biochemical modifications to the receptor, it separates from cytoplasmic chaperone proteins, thereby exposing the nuclear localization sequences that result in the activation of the receptor and initiation of the biological actions of the hormone on the target cell. In addition, recent work has demonstrated new pathways of steroid signaling through orphan and cell surface receptors that contribute to more rapid, “non-nuclear” or non-transcriptional effects of steroid hormones, often involving G-pro…
Plexin-B1 activates NF-κB and IL-8 to promote a pro-angiogenic response in endothelial cells.
Background The semaphorins and their receptors, the plexins, are proteins related to c-Met and the scatter factors that have been implicated in an expanding signal transduction network involving co-receptors, RhoA and Ras activation and deactivation, and phosphorylation events. Our previous work has demonstrated that Semaphorin 4D (Sema4D) acts through its receptor, Plexin-B1, on endothelial cells to promote angiogenesis in a RhoA and Akt-dependent manner. Since NF-κB has been linked to promotion of angiogenesis and can be activated by Akt in some contexts, we wanted to examine NF-κB in Sema4D treated cells to determine if there was biological significance for the pro-angiogenic phenotype o…
Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D
Phosphatidylinositol 4-phosphate 5-kinase (PI(4)P5K) is a type I lipid kinase that generates the lipid second messenger phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and functions downstream of RhoA in actin organization. It is known to play an essential role in neurite remodeling, yielding a phenotype identical to that seen in cells treated with Semaphorin 4D (Sema4D), a protein that regulates proliferation, adhesion and migration in many different cell types. Plexin-B1, the receptor for Sema4D, activates RhoA in order to generate a pro-angiogenic signal in endothelial cells. Therefore, we looked in human umbilical vein endothelial cells (HUVEC) to determine if Plexin-B1 e…
Plexin-B1 and Semaphorin 4D Cooperate to Promote Perineural Invasion in a RhoA/ROK-Dependent Manner
Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles located in the surrounding stroma. It is a pathological feature observed in certain tumors, referred to as neurotropic malignancies, that severely limits the ability to establish local control of disease and results in pain, recurrent growth, and distant metastases. Despite the importance of PNI as a prognostic indicator, its biological mechanisms are poorly understood. The semaphorins and their receptors, the plexins, compose a family of proteins originally shown to be important in nerve cell adhesion, axon migration, and proper central nervous system development. Emerging evidence has demonstrated that these factors a…