Anti-Angiogenic and Anti-Cancer Effects by Targeting the Protein Kinase G Type-Iα (PKG-Iα) Signaling Pathway and its Downstream Effects on Expression of Inhibitor of Apoptosis Proteins, C-IAP1, Livin and Survivin

Ovarian cancer is often difficult to treat because of the development of resistance to many of the currently-used therapeutic agents (i.e. chemoresistance). The progression and chemoresistance of ovarian cancer can involve tumor angiogenesis, the development of new blood vessels bringing more blood and nutrients to the growing tumor. Tumor angiogenesis also involves the vascular endothelium-induced stimulation of cancer cell growth (1) and the higher expression levels of certain “cell survival proteins”, such as the Inhibitor of Apoptosis Proteins (IAPs, including c-IAP1, Livin and Survivin), which are expressed in both the proliferating cancer cells (2, 3) and the vascular endothelial cells involved in tumor angiogenesis (4)

Adamts1 responds to systemic cues and gates adipogenesis

Intuitively, excess caloric intake causes adipose tissue expansion. However, the signals and mechanisms by which this systemic trigger directs a local response in the adipose tissue are incompletely understood. Both hypertrophy of existing adipocytes and the generation of new adipocytes through differentiation of adipocyte precursor cells (APCs), contribute to adipose tissue expansion in response to changes in the diet. Ex vivo studies of this process elucidated an elegant network of mostly transcription factors that drive APCs through the differentiation (adipogenesis) process. Here we discuss our study that identified an Adamts1 signal as a glucocorticoid and diet responsive regulator of an extracellular relay system that modulates the initiation of this intracellular adipogenesis program in APCs. Furthermore, we describe how we applied sensitive tools that enable monitoring of endogenous APC activity to study the early response to high-fat diet in vivo

A glucocorticoid- and diet-responsive pathway toggles adipocyte precursor cell activity in vivo

Obesity is driven by excess caloric intake, which leads to the expansion of adipose tissue by hypertrophy and hyperplasia. Adipose tissue hyperplasia results from the differentiation of adipocyte precursor cells (APCs) that reside in adipose depots. Investigation into this process has elucidated a network of mostly transcription factors that drive APCs through the differentiation process. Using in vitro and in vivo approaches, our study revealed a signaling pathway that inhibited the initiation of the adipocyte differentiation program. Mouse adipocytes secreted the extracellular protease ADAMTS1, which triggered the production of the cytokine pleiotrophin (PTN) through the Wnt/β-catenin pathway, and promoted proliferation rather than differentiation of APCs. Glucocorticoid exposure in vitro or in vivo reduced ADAMTS1 abundance in adipocytes. In addition, mice fed a high-fat diet showed decreased Adamts1 expression in the visceral perigonadal adipose depot, which expanded by adipogenesis in response to the diet, and increased Adamts1 expression in the subcutaneous inguinal adipose depot, which did not induce adipogenesis. Similar to what occurred in mouse subcutaneous adipose tissue, diet-induced weight gain increased the expression of ADAMTS1, PTN, and certain Wnt target genes in the subcutaneous adipose depot of human volunteers, suggesting the relevance of this pathway to physiological adipose tissue homeostasis and the pathogenesis of obesity. Thus, this pathway functions as a toggle on APCs, regulating a decision between differentiation and proliferation and coordinating the response of adipose tissue to systemic cues